2021–2022 Student Projects
Director’s Welcome
By all measures, QIMR Berghofer is one of the leading medical research institutes in Australia. Our mission is to deliver ‘better health through medical research’, and we do that by developing new diagnostics, better treatments and more effective strategies to prevent disease.
Research at the Institute is channelled through 4 This booklet gives an insight to the world that awaits clinically relevant programs, specifically in the areas of you at QIMR Berghofer. The projects presented within Cancer, Infectious Diseases, Mental Health and Chronic this booklet can often be adapted to suit your particular Disorders. The Institute is home to more than 700 staff skills and strengths, so I encourage you to talk to the and students who consistently generate formidable, Faculty members about any projects that take your high-quality research. Each year, our work gives rise to interest and find one that works for you. Lastly, I always more than 700 publications, around 40,000 citations, advise prospective students to ‘shop around’. You are and more than $10 million in commercial income. making a big decision, so you want to be sure that you are enthusiastic and inspired by the project you end up As a student at QIMR Berghofer, you will be joining an pursuing. elite cohort of exceptionally talented young scientists from around the globe. You will work alongside leading I hope you choose QIMR Berghofer as your next home investigators in state-of-the-art laboratories. You will and, if so, I look forward to welcoming you to this attend seminars showcasing the latest research findings, Institute for the next step in your academic career. and you will be encouraged to ask questions and help find answers to some of the world’s most pressing problems. While here, you will be well supported by a professional team who will help you to navigate your chosen academic path. In addition, you will receive mentoring advice and acquire the skills you need to pursue research to the highest levels of integrity and Professor Fabienne Mackay, Director and CEO, scholarship. QIMR Berghofer Medical Research Institute
QIMR Berghofer 2021 – 2022 Student Projects 3 Table of Contents
Directors Welcome Message 3 Investigating clinical practice relating to support for family carers of people with pancreatic cancer 18 Contents Page 4 Supportive care needs of carers of people Quick facts about QIMR Berghofer 7 with pancreatic cancer 18 QIMR Berghofer Student Committee 8 Molecular Cancer Epidemiology Group 18 Why study at QIMR Berghofer? 8 Evaluation of variants in known or QIMR Berghofer Services 9 candidate high-risk cancer genes 18 Histology Facility 9 Screening of genetically identified compounds Sample Processing 9 for endometrial cancer therapy 19 Flow Cytometry and Microscopy 9 Identifying the regulatory targets of common endometrial cancer risk variants 19 DNA Sequencing 9 Genetic Epidemiology of Endometrial Cancer 20 Analytical Services 9 Functional Cancer Genomics and Genome Informatics 9 Functional Genetics Group 21 QIMR Berghofer Facilities 10 Identifying new long-noncoding RNAs QIMR Berghofer Statistics Unit 10 involved in Breast Cancer development 21 Q-Gen Cell Therapeutics 10 Identification and evaluation of new melanoma risk genes 22 GenomiQa 10 Cancer Genetics Group 22 Medical Research Opportunities 11 Identifying the casual genes at cancer risk loci 23 Quick admissions guide for students 12 Oncogenomics Group 23 CANCER PROGRAM 13 Investigating SF3B1 in DNA damage response and sensitivity to PARP inhibitors 24 Cancer Control Group 14 Clinical Genomics Group 24 QSKIN: the burden of skin cancer 14 Exploring the mutational basis for Cancer Aetiology and Prevention Group 15 cancer-specific isoform expression 25
The D-Health Trial 15 Cancer Precision Medicine Group 25 Balancing the risks and benefits of sun Micropeptides produced by cancer cells exposure 15 and their role in tumorigenesis 25 Reducing diagnostic delay in patients with Plasma protein biomarkers to predict pancreatic cancer 15 immunotherapy response in lung cancers 26 Health Economics Group 16 Novel approaches to augment immunotherapy response in cancers 26 The risks and benefits of sun exposure: striking the right balance 16 Medical Genomics Group 27 Financial distress after cancer – developing Long read sequencing to extend genomic and testing a new survey 16 characterisation of cancer 27 Gynaecological Cancers Group 17 Regulation of DNA damage repair in cancers with defective homologous recombination pathway 28 Ovarian cancer – lifestyle, survival and quality of life 17 Complex neoantigen prediction in cancers 28
4 QIMR Berghofer 2021 – 2022 Student Projects Immune Targeting Blood Cancers Group 29 Drug Discovery Group 39 Targeting immuno-oncology molecules Investigating the anti-cancer activity of the in blood cancers 29 Epoxytigliane family 40
Translational Cancer Immunotherapy Group 29 Epigenetics and Disease Group 40 CAR T cells - redirecting T cells for Determining the therapeutic efficacy of cancer immunotherapy 30 epigenetic drugs in ovarian cancer 40
Gordon and Jessie Gilmour Leukaemia Combining epigenetic drugs with Research Group 30 immunotherapy in melanoma 41 Characterising biomarkers of resistance and Conjoint Gastroenterology Group 42 response to standard and novel therapies in Colorectal Cancer – from Genetics to Acute Myeloid Leukaemia 31 Chemoprevention 42 Antigen Presentation and Immunoregulation 31 Genetic changes underlying colorectal The role of IL-17 signalling in monocytes and cancer initiation and progression 42 macrophages in promoting cGVHD 32 Translational Cancer Discovery Group 43 Characterization of the effects of cGVHD on Enhancing the efficacy of conventional microglial function and the impact on immunotherapies 43 neurogenesis and cognitive function. 32 Development of new bi-functional antibodies Immunopathology Group 33 for the treatment of Head and Neck Squamous Modulating donor T cell polarisation after Carcinoma (HNSCC) 44 bone marrow transplantation to prevent Role for specialised lymph node cells in cancer graft-versus-host disease 33 immunity 44 Characterising miRNA expression after bone marrow transplantation to develop novel therapeutics 33 INFECTIOUS DISEASES Boosting immune checkpoint regulation to prevent/ PROGRAM 45 limit GVHD after allotransplantation 34 Molecular Parasitology Group 46 Inflammation Biology Group 34 Establishment of a CRISPR-Case9-mediated Sorting out the granzyme A and Nnt mess 34 gene knock-down system in Schistosoma japonicum targeting the acetylcholinesterase gene 46 Testing new interventions against SARS-CoV-2/COVID-19 using mouse models 35 Development of new interventions including vaccines, DNA diagnostics and serological Translational and Human Immunology Group 35 markers essential for ending neglected tropical diseases caused by schistosomes and COVID-19 immunity – Identifying memory intestinal worms in Asia and Africa 46 T cell protection against SARS-CoV-2 35 New interventions to end neglected Tumour Immunology Group 36 tropical diseases in Asia 47
Adoptive T-cell therapy for HPV associated Immunology and Infection Group 47 cancers 36 Discovering novel immunoregulatory molecules Improving the efficacy of T-cell therapy in vivo 37 that can be manipulated for clinical advantage 47 Cellular immunotherapy – engineering “custom built” cells to treat cancer 38 Human Malaria Immunology Group 48 Single cell genomic technologies in human malaria immunology 48
QIMR Berghofer 2021 – 2022 Student Projects 5 CHRONIC DISORDERS MENTAL HEALTH PROGRAM 49 PROGRAM 57
Hepatic Fibrosis Group 50 Psychiatric Genetics Group 58 Assessing the role of extracellular vesicles in the Assessing the cost and impact of Attention progression and development of drug resistance Deficit Hyperactivity Disorder in Australia 58 in prostate cancer 50 The role of genomics in understanding MicroRNAs as ant-fibrotic agents to treat liver psychiatric and neurological disease 58 scarring, fibrosis and cirrhosis in chronic liver Health and wellbeing in people with bipolar disease 50 disorder 58 Anti-inflammatory small molecule inhibitor Identifying risk factors for problematic internet development to control liver inflammation use and video gaming in Australian adults 59 associated with hepatic fibrosis in chronic liver disease 50 Brain Modelling Group 59 Iron Metabolism Group and Modelling brain dynamics across the lifespan 59 Molecular Nutrition Group 51 Novel methods for monitoring brain activity Developing improved methods for assessing in preterm babies 60 iron status 52 Translational Neurogenomics Group 60 Mucosal Immunology Group 53 The interplay between environmental and Prevention of allergy development in neonates genetic risk factors in the aetiology of by manipulating the microbiome 53 substance use disorders 60 Influence of early life parasitic infection on Integrating genomic data to characterise infant gut microbiome 53 inherited risk factors for mental health disorders 61 Hookworm-derived polypeptides for the Genetic Epidemiology Group 62 treatment of chronic diseases 53 Dissecting the genetic basis of clinical Respiratory Immunology Group 54 heterogeneity and differences in treatment response in patients with depression 62 Insights into the influence of maternal diet on the severity of infant viral bronchiolitis 54 Genetic and epidemiological studies of Parkinson’s disease 63 Microbiome and neonatal immune development in early life 54 Identifying individuals at high risk of Alzheimer’s disease 63 Eicosanoids and viral exacerbations of chronic obstructive pulmonary disease (COPD) 54 Cellular and Molecular Neurodegeneration Group 64 Cell death pathways and the induction of type-2 inflammation 54 Development of metal-based therapeutics for neurodegenerative diseases 64 Statistical Genetics Group 55 Generating patient-derived microglia to Genetics of skin cancer 55 investigate neuroinflammation in MND 65 Eye disease genetics 56 Generating Alzheimer’s microglia for testing patient responses to immune-modulating compounds. 65 B-lymphocytes in Autoimmunity and Malignancies Group 56 Olfactory stem cells for investigating the causes and progression of dementia 65 Discovering novel immunoregulatory molecules underlying the pathogenesis of systemic lupus Investigating blood-brain barrier mediated erythematosus 56 drug delivery in neurodegenerative diseases 66 3D Alzheimer’s disease ‘brain on a chip’ 66
6 QIMR Berghofer 2021 – 2022 Student Projects Quick facts about QIMR Berghofer
QIMR Berghofer QIMR Berghofer Medical Research is a world leading Institute was translational research established in institute focused on 1945. cancer, infectious diseases, mental health QIMR Berghofer and a range of chronic is home to more than disorders. 700 scientists (of which approximately 150 are students) in over 60 separate research groups.
The QIMR Berghofer student The logo of the QIMR Berghofer body is very Institute contains multinational and they three superimposed are strongly supported hexagons, representing by a Higher Degrees benzene rings, which are Committee dedicated to the molecular structure mentoring and guiding of carbon and the basis to all life. students through their candidature.
QIMR Berghofer 2021 – 2022 Student Projects 7 QIMR Berghofer Student Committee
Welcome Future Medical Why study at QIMR Berghofer? Leaders! Studying at QIMR Berghofer provides students with a unique opportunity to have access to diverse clinical and We are the QIMR Berghofer Student Committee, cutting edge research. Our proximity to RBWH and the your gateway to social aspects of your time within the Herston Campus makes us ideal for clinical research Institute. Our responsibilities include organisation of collaborations. social and fundraising events for all QIMR Berghofer Students through though the year, including Christmas In addition to your research training, QIMR Berghofer Party, Easter Egg Hunt, BBQs, movie nights, coffee meet is committed to your overall professional development. ups, bake sales or an International Food Day. We also This includes expanding your skills in critical scientific aim to develop some core skills for your future benefit by writing, statistics, leadership, communication skills, organising a student retreat, a conference format event understanding, and protecting your intellectual property. to meet your fellow students and interact with industry Your broader skill base, due to studying at QIMR representatives as well as development seminars. Berghofer, will allow you to compete for your future desired career. Student Committee is one of the three committees representing students within QIMR Berghofer, the other Advantages of studying at QIMR Berghofer include: two are the Higher Degree Committee (HDC) and the • Expert supervision from world leaders in their field of Seminar Convenors. research. The HDC student representatives provide feedback • Access to and support from high quality purpose built and concerns from students directly to the HDC panel, facilities and technical experts. consisting of senior scientists from QIMR Berghofer. Therefore, if you have any comments or questions they • Access to advanced technologies and equipment. are the ones to contact. Their further role is to organise a • Exposure to a wide range of interdisciplinary research yearly student symposium to enhance your presentation (population studies, statistics to public health and skills and network with other researchers within the tropical medicine to immunology and cancer). institute as well as bringing to you a range of workshops and welcome orientation sessions. • Opportunities for international collaboration and travel. The Seminar Convenors are in charge of the Early • Competitive Honours and PhD top-up scholarships. Career Research Seminar Series hosted every Friday. • Travel support available for attending international Those seminars are for you to practise your scientific conferences to promote collaborations and future communication abilities in a supportive environment and postdoctoral positions. to catch up with other students over some food and drinks. • Student mentoring and professional development. QIMR Berghofer is a fun, engaging and supportive • Dynamic process of review to monitor student community and a hub for a world-class research. What progress and ensure timely completion of your degree. else could you ask for when considering • A regular student seminar program. your next career step? • Weekly seminar series presented by QIMR Berghofer researchers, national and international speakers. • An active student society, student symposium and student retreat for networking and training purposes. The QIMR Berghofer student body is a diverse group of Australian and international students involved in a wide range of research endeavours. Make a real difference to directly relevant health issues for Australians and the rest of the world.
8 QIMR Berghofer 2021 – 2022 Student Projects QIMR Berghofer Services HISTOLOGY FACILITY The QIMR Berghofer Histology Facility is a fully equipped service and research laboratory. The facility caters to the DNA SEQUENCING needs of scientists and postgraduate students from QIMR The QIMR Berghofer DNA Sequencing Facility enables Berghofer as well as external and international institutions. both Next Generation and Sanger sequencing to deliver The unit provides technical services and also trains and high quality and reproducible data. This facility caters to consults on matters relating: the needs of scientists and postgraduate students from • Routine paraffin and cryo histology QIMR Berghofer as well as external and international institutions. The facility provides technical services and • Special stains also trains and consults on matters relating to Sanger (Big • Immunohistochemistry (Tyramide Signal Amplification) Dye) sequencing and Next Generation Sequencing (NGS). and antibody optimisation ANALYTICAL SERVICES • FISH and CISH labelling QIMR Berghofer Analytical Services contain fully equipped • Tissue preparation and sectioning for transmission service and research laboratories, enabling delivery of high electron microscopy and high-resolution digitisation of quality and reproducible data. Analytical Services caters histology slides (e.g. Vectra Imaging System). to the needs of scientists and postgraduate students The facility stocks a broad selection of commonly used from QIMR Berghofer as well as external and international primary antibodies and secondary detection antibodies institutions. The facility provides technical services and to label mouse, rat, rabbit, goat, sheep, hamster, guinea also trains and consults on cell line authentication, culture pig and chicken primary antibodies with horseradish media services unit, glassware and waste disposal. peroxidase, alkaline phosphatase, Alexa fluorescent or Tyramide (TSA) markers. GENOME INFORMATICS The Genome Informatics Group works on the analysis of SAMPLE PROCESSING next-generation sequencing (NGS) data and its research The Sample Processing Facility provides support to and clinical applications, particularly with respect to facilitate high throughput medical and epidemiological cancer. Cancer is increasingly being viewed as a disease research. Specimens are efficiently processed to produce where the tissue of origin is less important therapeutically the highest-quality product possible for downstream than the unique spectrum of mutations found in the experiments and/or analysis. individual patient’s tumour. NGS is the key technology used to catalogue mutations in both DNA and RNA and FLOW CYTOMETRY AND MICROSCOPY while it has been a research staple for over five years, it is only now starting to make inroads into the clinic. NGS is The Flow Cytometry and microscopy core facility provides a high-throughput genomics technology with significant world-class support service for scientists at QIMR computational and storage requirements – the data for Berghofer. Thanks to the support of the Australian Cancer each tumour/normal sample pair can use up to half a Research Fund (ACRF), the facility has expanded and terabyte of disk to store and tens of thousands of CPU is now the ACRF Centre for Comprehensive Biomedical hours to analyse. Imaging. We endeavour to stay up-to-date with ongoing acquisition of equipment, techniques and analysis software to meet the needs of the facility customers. As the facility is held in high regard, our services are sought not only by QIMR Berghofer scientists but those in the broader south- east Queensland region, Australia and overseas.
QIMR Berghofer 2021 – 2022 Student Projects 9 QIMR Berghofer Facilities
QIMR BERGHOFER STATISTICS UNIT Q-Gen Cell Therapeutics has expertise in and is TGA-licensed for human cell and cellular product The QIMR Berghofer Statistics Unit is comprised of ten development and production, quality-control testing: statisticians, who provide statistical consultancy and microbial contamination; endotoxin; Mycoplasma; flow research collaboration services to medical and clinical cytometry cell viability and identification and regulatory researchers. Services range from laboratory research documentation development. through to clinical trials, epidemiology and biomarker development. We can help you with: the formulation of research questions; study design; analysis plans; GENOMIQA power and sample size calculations; writing research GenomiQa specialises in somatic and germline analysis grants and protocols; data management plans; analysis of whole genome, whole exome and RNA sequencing. using statistical methods appropriate for medical and GenomiQa’s bioinformatics analysis software and health research; presentation and interpretation of data processes were developed and refined with quality as and analysis; preparation of and co-authorship on a guiding principle. Our founders based the services publications; addressing reviewers’ comments; expertise provided on robust research published in top-tier, peer- in design and analysis of clinical trials; public health and reviewed scientific journals, such as Nature. GenomiQa’s epidemiology; laboratory methods development and analysis pipelines are flexible, custom-made and validation; animal studies; and PK/PD modelling. customisable. Big data analytical services, from genomic sample preparation through to clinical interpretative Q-GEN CELL THERAPEUTICS reports, can be provided to pharmaceutical and biotechnology companies, researchers, clinical research Q-Gen Cell Therapeutics provide world-class facilities for organisations and pathology service providers. the manufacture of cellular therapies to GMP standards. Our experienced team can support your research from discovery through phase I clinical trials, to phase II and beyond.
10 QIMR Berghofer 2021 – 2022 Student Projects Medical Research Opportunities
Join one of the largest Medical Research Institutes in Australia. The options for students to be part of QIMR Berghofer are:
Research Higher Degree Student at QIMR Berghofer Medical Research Institute (PhD, MPhil, Masters Coursework or Honours) A We have a wide range of student projects, many that can be tailored to a student’s research interests. Some projects have the flexibility required for clinical students.
Vacation Research Programs Through University of Queensland, QUT and Griffith University, we offer vacation research experience. These B are small projects carried out over a 4-10 week period during the University summer (November-February) or winter (UQ only) vacation breaks giving student’s research experience and some financial support.
Volunteer Program Students who have an interest in medical research and would like to gain some research experience C can apply to be a research volunteer. This is not associated with any University course. These unpaid placements are for a limited period of time and acceptance is at the discretion of QIMR Berghofer.
General info: www.qimrberghofer.edu.au University Students Webpage: www.qimrberghofer.edu.au/education/for-university-students/ Projects Webpage: https://www.qimrberghofer.edu.au/student-projects/ For further enquiries, please contact: [email protected]
QIMR Berghofer 2021 – 2022 Student Projects 11 Quick Admissions Guide for Students
Check you are eligible for the degree you are interested in undertaking; this is specific to the 1 University you are enrolling through.
Check the QIMR Berghofer website and identify a student project or Research Group that 2 matches your research interests.
3 Contact the QIMR Berghofer scientist via email providing the following information: i) Whether you want to undertake MPhil or PhD study. ii) Discuss your research interests and any previous research experience. iii) Provide your academic CV.
Arrange to meet in person or have a Skype interview. If a supervisor accepts you as a student, 4 then continue the rest of the steps below.
5 Enrol through an Australian University.*
Complete the admission process to QIMR Berghofer. 6 An approval notification will be sent via email to you.
International students must also have an appropriate visa from the 7 Department of Home Affairs and Citizenship. #
Provide evidence of full admission/enrolment to an Australian University and Scholarship 8 (if you are joining the PhD program).
Congratulations, you are ready to begin your candidature.
PLEASE NOTE: This is only a BRIEF GUIDE and it is your responsibility to familiarise yourself with the details or requirements for each step. *IMPORTANT: Apply for admission to QIMR Berghofer and your chosen university at the same time. Many university departments will not approve your application until you have at least provisional approval from QIMR Berghofer. # This process may take up to 12 weeks to finalise, and this should be taken into consideration when determining your start date.
12 QIMR Berghofer 2021 – 2022 Student Projects Cancer Program Cancer is a leading cause of death in Australia. Sadly, nearly 50 000 Australians will die from cancer each year.
In 2019, it is estimated that almost 145,000 new cases of QIMR Berghofer cancer researchers aim to develop cancer were diagnosed in Australia (excluding basal and new strategies that will prevent, detect and treat squamous cell carcinoma of the skin). Cancer accounted cancer by: for about three in 10 deaths in Australia, making it the • PREVENTION: identifying specific modifiable second most common cause of death, exceeded only by environmental and genetic factors that reduce a cardiovascular disease. person’s risk of developing cancer Although overall cancer survival rates have improved in • DETECTION: developing better screening tests, the past 20 years, several types of cancer have poor so cancer can be detected earlier five-year survival rates. These include ovarian, brain, oesophageal, lung, pancreas and colorectal cancer. • TREAT: identifying better treatments for cancer and conduct clinical trials to test for effectiveness Cancer is a disease caused by abnormal cell growth and eventually spreads to other parts of the body. Some cancers are common within a family history and are clearly inherited, while others are caused by factors in the environment interacting with genetic susceptibilities. Many forms of cancer can be treated successfully, if detected early.
QIMR Berghofer 2021 – 2022 Student Projects 13 POPULATION HEALTH DEPARTMENT
Cancer Control Group QSKIN: the burden of skin cancer Group Leader: Supervisor: Professor David Whiteman Dr Catherine Olsen +61 7 3362 0279 +61 7 3362 0224 [email protected] [email protected] https://www.qimrberghofer.edu.au/our- research/cancer/cancer-control/ Suitable for PhD students only. Research undertaken by the Cancer Control Group is The QSkin study is a longitudinal cohort study established conducted with a view to reducing the burden from with the primary aim of deriving measures of absolute and cancer through identifying risk factors, then translating relative risk for basal cell carcinoma (BCC), squamous these research findings into policy and practice. This cell carcinoma (SCC) and melanoma associated with includes research to identify the environmental and phenotypic, genetic, clinical, and environmental factors. genetic factors that cause cancer, as well as research into Secondary aims were to estimate the burden (treatments, early diagnosis, treatment and survival. hospitalisations, direct and indirect costs, mortality etc.) of skin cancer; quantify the effects of protective behaviours; The group had two major areas of research focus: and develop tools for predicting risk of melanoma and melanoma and skin cancer, and upper gastrointestinal other skin cancers. The cohort was established in 2010 neoplasia. and comprises of 43,794 men and women aged 40-69 years sampled randomly (in strata of age and sex) from the Queensland Electoral Roll. Participants completed a baseline survey and gave consent for record linkage to the Queensland Cancer Registry (QCR), Medicare (MBS/ PBS), pathology providers (private and public) and the Queensland Hospital Admitted Patient Data Collection. These linkages ensure virtually complete follow-up of all clinical events in the cohort. In 2015, 18,000 participants provided a saliva sample and these have been genotyped on the Illumina Global Screening array. We are seeking highly motivated PhD students with experience in data analysis who are interested in undertaking a project related to skin cancer. These may include (but are not limited to): • Health services research • Pharmaco-epidemiology • Mendelian randomisation (MR) analyses • The genetics of multiplicity (i.e. susceptibility to many tumours) • Gene/environment interactions in the aetiology of skin cancer • Dietary/lifestyle factors in the aetiology/prevention of skin cancer
14 QIMR Berghofer 2021 – 2022 Student Projects CANCER PROGRAM
Cancer Aetiology and The D-Health Trial Some components of this project are suitable for Prevention Group Honours students, flexible for clinical students and Group Leader: Associate entire project is suitable for PhD students. Professor Rachel Neale The D-Health Trial is a large (N=~21,000) randomised placebo-controlled trial that aims to determine whether +61 7 3845 3598 [email protected] population-level supplementation with vitamin D influences mortality, cancer, cardiovascular disease and a https://www.qimrberghofer.edu.au/our- wide range of other outcomes. research/cancer/cancer-aetiology-and- prevention/ Projects are available for Honours, Masters, or PhD level students with an interest in public health, nutrition, or The Cancer Aetiology and Prevention Laboratory covers statistical analysis. Students must have experience using three broad research areas: causes and management statistical packages such as SAS, R or STATA. There will of pancreatic cancer, the role of vitamin D in human be some scope to choose which outcome/s will be the health, and causes and management of non-melanoma focus of the project. skin cancer. A/Prof Neale and her team have published a series of papers describing inequity in management Balancing the risks and benefits of sun of pancreatic cancer according to sociodemographic exposure factors, and the very high supportive care needs of patients. She is now investigating ways to deliver better Some components of this project are suitable for supportive care to these vulnerable patients. Honours students, flexible for clinical students and entire project is suitable for PhD students. A/Prof Neale is the principal investigator of the D-Health Trial, the second-largest trial of high-dose vitamin D The sun causes skin cancer, but is also the main source supplementation in the world. Over 21,000 adults were of vitamin D. It is difficult to advise the general public enrolled and randomised to vitamin D or placebo, taken about how much sun exposure to receive to find the monthly for 5 years. The intervention phase continued balance. This project will involve using published literature, until May 2020. This project will generate data to inform along with UV readings for Australia, to identify different policy makers and clinicians about the benefits or patterns of sun exposure that will minimize the risk of otherwise of population-wide vitamin D supplementation vitamin D deficiency and cancer. The student will also and will also provide a platform for the training of multiple have the opportunity to explore the best methods to students. communicate this complex message. This project would suit a student with an interest in both quantitative and Co-supervisors: qualitative research, and requires excellent mathematical Dr Mary Waterhouse and communication skills. +61 7 3845 3560 [email protected] Reducing diagnostic delay in patients with pancreatic cancer Suitable for PhD students. Dr Bridie Thompson Pancreatic cancer is difficult to diagnose and many +61 7 3362 0296 patients describe diagnostic delay. However, the extent, [email protected] causes, and consequences of diagnostic delay in Australia are not well understood. This project will involve interviews with patients and their families, along with analyses of linked data, to explore this issue and devise potential methods to optimize the diagnostic journey for Australian patients.
QIMR Berghofer 2021 – 2022 Student Projects 15 The risks and benefits of sun exposure: Health Economics striking the right balance Group This project can be adapted for PhD or Honours study. Team Head: Associate Professor Sun exposure has both harms and benefits. Over- Louisa Gordon exposure to the sun’s ultraviolet radiation (UVR) is the +61 7 3845 3717 primary cause of skin cancer but the main source [email protected] of vitamin D. We currently do not provide accurate, evidence-based, clear and appropriate public health https://www.qimrberghofer.edu.au/our- messages about optimal sun exposure. There are research/cancer/health-economics/ substantial challenges in doing so due to the complexity The Health Economics team has operated since May in the scientific evidence around UVR measurement, 2016. Research has focused on economic evaluations environmental factors (time of day, season, location, and decision-modelling of healthcare interventions that weather, climate change), social factors (outdoor span a wide range of health conditions and populations. exposure, intentional tanning, attitudes to sun protection), The lab has three main themes of applied health individual factors (skin phenotypes, medication use, economics: cancer control strategies (from prevention immunity) and economic factors (markets for sunscreen/ through to treatments), clinical genomics and measuring tanning, vitamin supplements, medical services). Too high low-value healthcare. or too low sun exposure exerts an enormous disease and economic burden on society that we currently do not Economic evaluations in health care involve systematically fully understand because the dual problems have never assessing the costs and patient outcomes of new been jointly assessed. There are a range of tasks that are services and technologies to determine their cost- needed to address this question: systematic reviews on effectiveness or value for money. This usually involves specific components, developing a systems model for both short-term ‘within-trial’ analyses and long-term data simulations, generating data on costs of sun-related decision-analytic modelling. Ultimately, this work assists diseases and potential interventions to model. Large in the translation of experimental research of effective datasets are also available to analyse individual-level data, interventions into clinical practice so that effective services which will contribute to our knowledge on this dual health also demonstrate good economic value or sustainable problem. cost-savings. The team also highlights areas of economic inefficiency where healthcare resources are misused Financial distress after cancer – and assesses the economics of the important role that disease prevention initiatives have on population health. developing and testing a new survey This project can be scaled appropriately for PhD or Honours study. The term ‘financial toxicity’ is broadly used to describe the distress or hardship arising from the financial burden of cancer treatment. In much the same way as physical side effects of treatment like fatigue, nausea or blood toxicities, financial problems after cancer diagnosis are a major contributor to poorer quality of life, treatment non-adherence and delayed medical care. Currently there is no data collection tool that can assess the financial stress after cancer comprehensively, and include out-of- pocket expenses, impacts to work life and work income and issues like forced early retirement. This project aims to develop and test a new data collection instrument that can be used to capture this important quality of life issue. The project would involve literature searches, developing a survey, recruiting participants via social media, administering the survey and data analysis.
16 QIMR Berghofer 2021 – 2022 Student Projects CANCER PROGRAM
Gynaecological Ovarian cancer – lifestyle, survival and quality of life Cancers Group Co-supervisor: Associate Group Leader: Professor Vanessa Beesley Professor Penny Webb +61 7 3362 0270 +61 7 3362 0281 [email protected] [email protected]
https://www.qimrberghofer.edu.au/our- The projects would be suitable for Masters (preferably research/cancer/gynaecological-cancers/ part-time), Honours or PhD students but some About 1500 women are diagnosed with invasive ovarian experience in statistics and data analysis is essential cancer in Australia every year and five-year survival is and a background in epidemiology and/or an interest in still less than 50%. About 3000 women are diagnosed cancer are highly desirable. with endometrial cancer. Both the cancers and the AIMS: A wide range of data is available covering lifestyle, treatment for them can affect a woman’s quality of life. To patterns of care, quality-of-life and survival. Potential reduce incidence we need better information about what projects include, but are not limited to: causes the cancers and who is most at risk. To improve outcomes we need to ensure that all women get optimal • Quantifying use of complementary medicines by care, increase understanding about the problems that women with ovarian cancer and whether this is women experience and identify factors that can improve independently associated with patient outcomes prognosis. including wellbeing, quality of life, progression-free and overall survival. [Supervisor Penny Webb] The Australian Ovarian Cancer Study (AOCS) collected information about potential risk factors, quality of life • Investigating the distress and supportive care needs of and survival and the Ovarian Cancer Prognosis and family carers of women with ovarian cancer [Masters/ Lifestyle (OPAL) study has followed a national cohort of Honours (or possible PhD if extended to pancreatic women newly diagnosed with ovarian cancer for up to 8 cancer); Supervisor Vanessa Beesley] years. Both of these studies also contribute data to the • Determining symptoms in women with ovarian cancer international Ovarian Cancer Association Consortium before end-of-life [Masters/Honours; Supervisor (OCAC). In addition, the IMPROVE Study has linked Vanessa Beesley] routine health data for all women diagnosed with ovarian cancer in Australia and future studies are planned to • Identifying clusters of symptoms (cognitive impartment, build on this. The Australian National Endometrial Cancer fatigue, sleep, neurotoxicity, pain) that predict poor Study (ANECS) has similar data for endometrial cancer long-term quality of life [Masters/Honours; Supervisor and is also a part of the international Epidemiology of Vanessa Beesley] Genetics & Computational Biology Endometrial Cancer Consortium (E2C2). Department
QIMR Berghofer 2021 – 2022 Student Projects 17 Investigating clinical practice relating to support for family carers of people Molecular Cancer with pancreatic cancer Epidemiology Group The project would be suitable for MPhil or Honours Group Leader: Associate students. Professor Amanda Spurdle In hospitals, patients are the focus of care, they have a +61 7 3362 0371 UR number and hospitals can bill for their care; this is [email protected] not the case for carers. Family carers of patients with https://www.qimrberghofer.edu.au/ pancreatic cancer are confronted with the need to assist our-research/cancer/molecular-cancer- in the management of complex physical symptoms. epidemiology/ Additionally they face the impending loss of their loved one and are twice as likely to experience anxiety as the The Molecular Cancer Epidemiology Laboratory studies patients they cared for. This project will involve interviews breast and ovarian cancer, endometrial cancer, colon with oncology staff and/or primary care practitioners cancer and prostate cancer, with a focus on identifying to gain insights into supportive care screening and the molecular signatures of normal and tumour tissue that support interface between acute and primary care of this can point to the genetic and environmental causes of population. Could also be combined with quantitative these cancers. The laboratory covers a range of projects analyses from existing studies in this population. with the themes of cancer epidemiology and molecular pathology. Supportive care needs of carers of people with pancreatic cancer Evaluation of variants in known or candidate high-risk cancer genes The project would be suitable for Coursework Masters or PhD students. Can be adapted in scope for Honours or PhD. Supportive care is a person-centred approach to the BACKGROUND: Panel gene testing is increasingly provision of the necessary services for those living with or applied to identify the underlying genetic cause of affected by cancer to meet their informational, spiritual, cancer in patients with suspected hereditary cancer. emotional, social, or physical needs. Pancreatic cancer Identification of a pathogenic variant directly influences is rare and deadly. This project will involve statistical clinical management for patients and their at-risk analysis of an existing dataset to document the unmet relatives, setting the path for preventative and increasingly supportive care needs specifically among carers of people chemotherapeutic options. Unfortunately, such testing with pancreatic cancer and to determine the risk factors often identifies variants with uncertain impact on function associated with having high-level unmet needs. and clinical phenotype. Such variants of uncertain clinical significance create considerable difficulties for counselling and clinical management. A range of methods can be useful for assessing variants, including bioinformatic analysis, assays of mRNA and protein function, and also investigating association with clinical features such as segregation in families, age at onset /phenotype in case- control studies and tumour pathology. AIM: To use statistical and laboratory methods to assess the clinical relevance of rare cancer gene sequence variants identified by clinical genetic testing of patients with suspected hereditary cancer, identified in Australia or through the international consortia such as ENIGMA.
18 QIMR Berghofer 2021 – 2022 Student Projects CANCER PROGRAM
APPROACH: This project will assess the effect of Three of these candidates are now undergoing a virtual variants on gene/protein function using a variety of small molecule screen, using artificial intelligence to bioinformatic predictions, molecular biological assays prioritise compounds. Additionally, we have performed and/or statistical analyses. Techniques may include bioinformatic analysis of GWAS data, revealing existing RNA analyses using LCLs and/or constructs, protein drugs that may have efficacy for endometrial cancer. assays in collaboration with other laboratories, pedigree AIM: To screen compounds, selected by artificial analysis and simple statistical analyses of clinical factors intelligence, for activity against candidate protein targets predictive of pathogenic variant status, to develop identified from endometrial cancer GWAS and assess the calibrated measures of association with disease for use in anti-cancer effects of prioritised compounds and existing multifactorial likelihood analysis. drugs for anti-cancer effects. OUTCOME: Analysis of specific variants will provide APPROACH: We will use commercially available and evidence regarding their pathogenicity for translation previously reported assays to screen for the effects of in the clinical setting. Comparison of assay results with compounds on the activity of candidate protein targets. risk will form the foundation for improving bioinformatic Compounds with the strongest effects in protein assays prediction tools and incorporating predictions and/ will be prioritised for assessment of anti-cancer effects or biological assay results in statistical models of risk in novel endometrial organoid models. Existing drugs prediction. identified through bioinformatic analysis will also be tested in organoid models. Screening of genetically identified compounds for endometrial cancer OUTCOME: Identification of novel compounds or therapy existing drugs that have anti-cancer effects in organoid models would provide the necessary evidence for further Supervisors: Associate development of these molecules, with the ultimate aim of Professor Dylan Glubb conducting clinical studies of endometrial cancer. +61 7 3845 3725, [email protected] Identifying the regulatory targets of common endometrial cancer risk Associate Professor variants Tracy O’Mara Suitable for PhD students only. +61 7 3362 0389, Our International Endometrial Cancer Association Tracy.O’[email protected] Consortium collaborators and we have identified common genetic variations at 16 genomic regions that associates Can be adapted in scope for Honours or PhD. with endometrial cancer risk. Although we have identified potentially causal risk variants, at most regions we do not There is promising evidence that genetic studies of cancer know which genes these variants target. However, we will advance the development of new therapies. For have conducted global (HiChIP) analyses of DNA looping example, clinically approved drugs are more likely to target to identify physical interactions between genes and proteins that have been linked to disease traits through regulatory elements at endometrial cancer risk regions genome-wide association studies (GWAS) than proteins in endometrial cancer cell lines. These experiments with no such links. Indeed, several drugs already used constitute an essential step for the translation of genetic to treat endometrial cancer are known to target proteins findings into advances in our knowledge of endometrial that have been linked to genetic variation associated with cancer biology and the identification of potential targets endometrial cancer risk. To discover genes regulated by for therapy. endometrial cancer GWAS variants, and hence potential drug targets, we have performed functional genomic analyses of endometrial cancer. These analyses revealed candidate targets tractable to small molecule inhibition.
QIMR Berghofer 2021 – 2022 Student Projects 19 AIM: To identify high confidence gene regulatory targets AIMS: To identify new genetic risk regions for endometrial of endometrial cancer risk variants using DNA looping cancer, by performing the largest GWAS meta-analysis for analyses and other functional genomic datasets. this disease. To use computational approaches to identify and explore risk factors of endometrial cancer. To use APPROACH: Depending on the applicant’s expertise, genetic data to construct and test risk prediction models this project could have either a wet-lab and/or a for endometrial cancer. bioinformatics focus. We already have a wealth of endometrial cell DNA looping data that can be coupled APPROACHES: This project will use standard GWAS with complementary datasets (gene expression, histone pipelines to identify genetic variants associated with modification and transcription factor ChIP-seq) for endometrial cancer risk, including imputation, QC and bioinformatic analyses to prioritise regulatory target genes. association testing. Post-GWAS analyses to explore novel To extend our findings from DNA looping analysis of regions could also be performed (e.g. eQTL analyses, endometrial cell lines, we are also interested in performing integration with functional genomic datasets). The analysis of human endometrial organoids from normal, relationship between endometrial cancer and potential/ hyperplastic and tumoural endometrium. These organoids known risk factors will be performed using approaches should provide experimental systems that will better such as genetic correlation (LD Score Regression) and recapitulate the morphological and genomic features of Mendelian randomization. Endometrial cancer risk human tissue. prediction models will be constructed using polygenic risk scores in combination with endometrial cancer OUTCOME: Through the identification of high environmental risk factors and tested for efficacy in confidence gene targets at endometrial cancer risk independent datasets. regions, we will gain a deeper understanding of endometrial cancer aetiology and identify potential targets for endometrial cancer therapy. Genetic Epidemiology of Endometrial Cancer Suitable for PhD students only. Endometrial cancer is the most commonly diagnosed invasive gynaecological cancer in developed countries. In contrast with many cancers, the incidence and mortality of endometrial cancer is steadily increasing, largely due to increasing rates of obesity, the strongest risk factor for this disease. Through leadership of the Endometrial Cancer Association Consortium (ECAC), our lab runs the largest genetic study of endometrial cancer. To date, we have identified 16 genetic regions associated with endometrial cancer predisposition by genome-wide association study (GWAS), which account for ~25% of the genetic heritability attributable to common genetic variants (O’Mara et al, Nat Commun 2018). Incorporation of existing GWAS data with newly acquired GWAS datasets from international collaborators will identify further genetic regions associated with endometrial cancer risk. Additionally, we have approved access to large, well- phenotyped international datasets (e.g. UK Biobank, N = 500,000). This allows us unparalleled ability to examine the genetics of endometrial cancer, as well as explore its relationship with risk factors, such as obesity.
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whole gene sequencing (WGS) can alter these non- Functional Cancer coding elements to promote the development of cancer. The ultimate aim is to use genetics to pinpoint the key Genomics & genes and pathways implicated in the development of Functional Genetics cancer to identify new therapeutic opportunities. Group Identifying new long-noncoding RNAs involved in Breast Cancer development Group Leader: Associate Professor Stacey Edwards Can be adapted in scope for Honours or PhD project. (Functional Cancer Genomics It is now clear the majority of the human genome is Group) transcribed from both DNA strands but only 2% encodes +61 7 3845 3029 protein. Much of this transcription is derived from DNA [email protected] sequences that do not encode functional proteins. The majority of these transcripts are long non-coding RNAs https://www.qimrberghofer.edu.au/ (lncRNAs) defined as being >200 bp in length. While it is our-research/cancer/functional-cancer- genomics/ generally accepted lncRNA transcription is functionally significant, the scope and function of lncRNAs in cancer The Functional Cancer Genomics Laboratory focuses on is still not well understood. In the last five years, genome understanding how DNA variation contributes to cancer wide association studies (GWAS) have identified 170 risk and development. The laboratory is particularly common variants (or SNPs) associated with an increased interested in translating the findings from genome- risk of breast cancer. Importantly, the majority of these wide association studies (GWAS) for breast, ovarian, disease-associated SNPs lie within intergenic regions and endometrial, prostate and skin (melanoma) cancers. within introns of protein-coding genes, suggesting that This includes identification of the causal risk variants, undiscovered RNA transcripts such as lncRNAs, may be connecting these variants to their target genes and responsible for the risk in a subset of breast cancers. We understanding how the new genes contribute to cellular have recently used a targeted RNA sequencing approach phenotypes associated with cancer development. We called RNA CaptureSeq to identify lncRNAs transcribed have already identified several molecular pathways that from breast cancer risk loci. This key experiment has were not known to play a role in cancer that are suitable identified hundreds of candidate breast cancer-associated targets for drug repositioning or drug development. The lncRNAs. ultimate aim of our research is to pave the way for future clinical trials for cancer prevention or treatment. In this project, we will use multiple in vitro approaches to identify lncRNAs whose expression is altered by Group Leader: Associate breast cancer risk SNPs. These include eQTL analyses, Professor Juliet French chromosome conformation capture (3C)-based (Functional Genetics Group) techniques and reporter assays. We will also generate +61 7 3845 3028 isogenic cell lines using CRISPR/Cas9 technology, which [email protected] will be used to measure lncRNA expression and identify allele-specific chromatin interactions. We expect that https://www.qimrberghofer.edu.au/our- some of the lncRNAs will have cancer-related biological research/cancer/functional-genetics/ functions. We will therefore overexpress or silence The Functional Genetics Laboratory investigates how lncRNAs in breast cells and examine their effects on genetic variants in noncoding regions of the genome cell proliferation, response to DNA damage, apoptosis, contribute to cancer risk and progression. Until recently, migration, invasion and tumour formation. We will the genetic basis of cancer has only been examined also assess the function of lncRNAs in breast tumour in coding regions, which accounts for less than 2% of formation using an explant assays in mice. The discovery the human genome. However, it is now apparent that of novel regulatory RNAs influencing breast cancer noncoding regions are littered with functional elements development may reveal entirely new avenues for breast such as transcriptional enhancers and long non-coding cancer therapeutics. Students will have access to unique RNAs. The laboratory focuses on how inherited variants expertise and reagents, and will acquire skills in tissue identified through genome wide association studies culture, CRISPR/Cas9, RNA manipulation, and other (GWAS) and cancer specific mutations identified through basic molecular biology techniques.
QIMR Berghofer 2021 – 2022 Student Projects 21 Identification and evaluation of new melanoma risk genes Cancer Genetics Suitable as a PhD project. Group Genome-wide association studies (GWAS) have Group Leader: Professor successfully uncovered new risk genes and new biology Georgia Chenevix-Trench for complex diseases resulting in a major push to translate +61 7 3362 0390 these findings to improve drug development. We want [email protected] to realise the promise of this approach in cutaneous melanoma (CM), the deadliest form of skin cancer. In the https://www.qimrberghofer.edu.au/our- last two years, GWAS have identified single nucleotide research/cancer/cancer-genetics/ polymorphisms (SNPs) across 56 regions associated In the Cancer Genetics Laboratory we investigate why with an increased risk of CM. Importantly, the majority some people get cancer, and how these cancers, of these risk SNPs lie within noncoding regions of particularly those of the breast and ovary, develop from the genome such as introns and intergenic regions. a normal cell. Using genome wide association studies Therefore, despite the significance of the genetic analyses (GWAS), we have identified 179 breast cancer (BC) additional functional studies are required to identify the risk loci. Through extensive in vitro assays, we and key genes targeted by the risk SNPs. Recent studies our collaborators have successfully identified some indicate that cancer risk SNPs are enriched in DNA of the target genes at 14 of these loci. The functional regulatory elements such as enhancers. Enhancers can mechanism behind the associations usually involves be located hundreds of kilobases from their target genes perturbed regulation of target gene transcription by risk and regulate transcription through long-range chromatin single nucleotide polymorphisms (SNPs) lying in regulatory interactions. The noncoding genome also serves as a elements positioned some distance from the target. The template for the transcription of long noncoding RNAs, nearest gene to the GWAS ‘hit’ is not necessarily the some of which are mutated in cancer initiation and target of the association, and for some loci there are progression. multiple gene targets. We have developed a pipeline for In this project, we will use a combination of high- predicting target genes at GWAS hits but the challenge throughput methodologies to comprehensively identify all of functionally interrogating each risk locus to identify the CM risk-associated enhancers and their target protein- target gene(s) is enormous. With our collaborator, Dr Sefi coding and noncoding RNA genes. These include Rosenbluh at Monash University, we are now planning targeted RNA sequencing, chromatin conformation- to perform large-scale pooled CRISPR knockout and based techniques, eQTL analyses and reporter assays. activation screens of all the predicted target coding and We will generate isogenic cell lines using CRISPR/Cas9 non-coding genes at these loci to identify novel breast technology, which will be used to measure target gene cancer risk genes. We are currently developing assays expression, identify allele-specific chromatin interactions to identify genes that affect proliferation, anchorage and assess transcription factor binding. We will also independence, senescence, tumorigenicity and examine the function of the new genes in cancer- immunosurveillance. In addition, we will comprehensively related pathways. Melanoma cells will be engineered to investigate breast cancer risk loci where the predicted overexpress or silence target genes, then assayed for target genes are known drug targets, with a view to cell proliferation, apoptosis, response to DNA damage developing novel risk reduction medications. and tumour formation using an explant assays in mice. We also have an interest in genes involved in response The outcomes of this project will represent a major to chemotherapy in ovarian cancer patients, and have breakthrough as the products of these genes may provide done a genome-wide association study in cases from new drug targets for future CM prevention or therapy. the Ovarian Association Consortium. This has identified Students will have access to unique expertise and a locus near the ULK1 gene, which is associated with reagents, and will acquire skills in tissue culture, CRISPR/ progression free survival in ovarian cancer patients. Cas9, DNA/RNA manipulation, and other molecular Further characterization of this locus is underway. biology techniques.
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Identifying the casual genes at cancer risk loci Oncogenomics Group Group Leader: Professor Co-supervisor: Nicholas Hayward Dr Jonathan Beesley +61 7 3362 0306 +61 7 3362 0388 [email protected] [email protected] https://www.qimrberghofer.edu.au/our- research/cancer/oncogenomics/ Suitable for PhD or Honours students. The Oncogenomics Laboratory identifies and Our laboratory is involved in genome wide association characterises novel cancer genes and studies the way studies to identify common variation underlying risk of in which defects in these genes are associated with breast and ovarian cancers. The current challenge is cancer predisposition or development, particularly with a in the functional interpretation of genetic association focus on melanoma and lung cancer. Some individuals data. With this aim, we use a variety of computational are at much higher risk of developing particular types of approaches to define potential molecular mechanisms at cancer than the general population because they carry an GWAS loci and to generate specific hypotheses to guide inherited mutation in one of many key cancer genes. The further experimental work. laboratory’s main approach is to carry out whole genome sequencing of members of families in which there is a Specific areas of interest include: high density of cancer to find gene variants that might be • Analysis of high throughput sequencing data such as responsible for the observed cancer predisposition. With ATAC-seq and HiChIP from primary breast samples and improved understanding of the genetic events underlying cultured cells cancer susceptibility, it is hoped this will lead to better • Integration of genetic and functional genomics data to ways of diagnosing or treating cancers in the future. predict target genes at GWAS loci • Mining of public epigenomic datasets such as those from the ENCODE and ROADMAP Consortia • Identification of candidates for drug repositioning • Analysis of CRISPR screen data Project would suit a bioinformatics student with an interest in gene regulation. Students would work closely with dry and wet lab scientists to identify cancer genes and pathways, which might represent targets for future drug development.
QIMR Berghofer 2021 – 2022 Student Projects 23 Investigating SF3B1 in DNA damage response and sensitivity to PARP Clinical Genomics inhibitors Group Co-Supervisor: Team head: Associate Professor Dr Kelly Brooks Ann-Marie Patch +61 7 33620308 +61 7 3845 3983; [email protected] [email protected] https://www.qimrberghofer.edu.au/our- research/cancer/clinical-genomics/ Suitable for Honours Students. In the Clinical Genomics lab, we analyse sequencing data SF3B1, a splicing factor component, has been found to using bioinformatic tools to investigate the mechanisms be mutated in subtypes of a number of cancers including that enable cancer cells to establish, multiply and become uveal melanoma (UM) (~15-24%), chronic lymphocytic resistant to treatment. leukaemia (CLL) (~17%) and mucosal melanoma (MM) (~10-37%), all of which need improved therapeutic Cancer is often described as a genetic disease because options. SF3B1 mutations in UM are known to be many cancers are caused by the accumulation of associated with metastatic disease and in CLL are linked mutations in the DNA of affected cells. Although treatment with poor prognosis. These mutations appear to be gain- of the primary cancer may initially appear successful, of-function with three specific hotspots occurring and unfortunately for many patients the cancer can come very few cases of nonsense or loss-of-function mutations. back (cancer recurrence) and/or spread to other organs Despite being a splicing factor, SF3B1 has also been (cancer metastasis). Over the last 10 years, international shown to interact with DNA and histones and has been networks of scientists have been working together e.g. identified as a hit in screens for DNA damage repair (DDR) The Cancer Genome Atlas (TCGA) and International genes. The role of SF3B1 in DDR is unclear however, and Cancer Genome Consortium (ICGC), to generate it is uncertain if the common hotspot mutations impact sequencing data from the DNA or RNA of cancer cells that role. Interestingly we have shown that cancer cell to find common underlying mutations. The results from lines with SF3B1 hotspot mutations are hypersensitive these studies have helped scientists to understand the to treatment with PARP inhibitors suggesting that they main driver mutations that commonly cause cancers may alter the DDR response. This project will look at but they have also highlighted the complexities of each determining the normal role for SF3B1 in the DDR individual cancer and that each person may respond response and determining if/how SF3B1 mutations alter differently to cancer treatments. this. This is important groundwork to provide evidence for One major complexity is termed “intra-tumour the use of clinically safe and available PARP inhibitors in heterogeneity” which means there exist subpopulations patients with SF3B1 mutant cancer. of cancer cells with genomic differences within one person’s disease. These subpopulations are referred to as sub clones and they can have distinct genetic, transcriptomic, epigenetic and phenotypic characteristics. Differences can also be observed between the sub clones identified from the primary disease and those identified from metastases that have spread to different organs. Thus, one of our objectives is to analyse sequencing data to identify patterns of gene mutation and expression between different deposits and sub clones of cancer that can contribute to the response of patients to their treatment.
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Exploring the mutational basis for cancer-specific isoform expression Cancer Precision
Co-supervisors: Medicine Group Dr Pamela Mukhopadhyay Group Leader: Associate Professor Harsha Gowda +61 7 3845 3966 [email protected] +61 7 3362 0452 [email protected] Dr Stephen Kazakoff https://www.qimrberghofer.edu.au/ our-research/cancer/cancer-precision- 0437 723 230 medicine/ [email protected] The Cancer Precision Medicine laboratory employs multi- disciplinary approach involving genomics, proteomics Can be adapted in scope for Honours, Masters or PhD and bioinformatics to characterize molecular alterations students. associated with various cancers. These alterations HYPOTHESIS: Some somatic mutations may alter the provide insights into mechanisms underlying molecular way a gene is expressed resulting in cancer- specific pathogenesis of cancers. They can also serve as isoform expression. biomarkers for identification and stratification of patient sub-groups that can benefit from targeted therapeutic AIM: The overall aim of this project is to integrate the intervention strategies. In addition, the lab works on mutational and transcriptomic data of individuals to detect delineating mechanisms of acquired resistance to kinase the differences in isoform usage between primary and inhibitors and devising novel strategies to combat metastatic disease. Exploring how DNA mutations may therapeutic resistance. result in altered gene transcription could explain why some cancer cells become resistant to treatment. Micropeptides produced by cancer This is a fully computational based project and will cells and their role in tumorigenesis suit a student with a strong interest and experience in computer programming. It will involve generating new Suitable for PhD Students. methods for integrating mutational data from whole- BACKGROUND: For several years, it is known that genome sequencing with both long-read and short-read human genome has ~20,000 protein coding genes. transcriptome sequencing. The project will require the Transcriptome sequencing studies in the past decade candidate to process long-read sequencing data to have revealed that a large portion of human genome is detect the isoforms expressed within multiple samples transcribed. However, most of it is thought to be non- from cancer patients. Analysis of matched short- coding. Recent studies have revealed that some of the read RNA-Seq data will be used for verification and annotated non-coding RNAs harbor small open reading development of methods to improve isoform identification frames that code for micropeptides/small peptides. from short-read data. Whole genome sequencing of We have previously discovered several small ORFs in matched samples will allow exploration of the mutational annotated non-coding RNAs and UTR regions of mRNAs basis for differences in expressed isoforms between (Nature. 2014 509(7502):575-81). Various studies in the the samples. The integrated datasets may provide last five years have demonstrated that micropeptides corroborative evidence of sub clonal heterogeneity that regulate several functions including development, muscle can be evaluated with clinical data to identify the sub performance and DNA repair. Ribosome profiling studies clonal characteristics of tumours that influence treatment (Ribo-Seq) have also revealed the possibility of many response. small open reading frames that could potentially code for micropeptides. It appears that several micropeptides encoded by human genome are yet to be discovered. Until then, various cellular functions regulated by these micropeptides and their role in various human diseases remains out of bounds for systematic investigation. HYPOTHESIS: Cancer cells produce micropeptides that are involved in regulating tumorigenesis
QIMR Berghofer 2021 – 2022 Student Projects 25 AIM: Identification of micropeptides produced by cancer • Targeted mass spectrometry and ELISA based cells methods to validate potential biomarkers APPROACHES: Novel approaches to augment • Cell culture immunotherapy response in cancers • Isolation of micropeptides from cancer cell lines Suitable for PhD Students. • Identification and characterization of micropeptides by mass spectrometry BACKGROUND: Immunotherapy has revolutionized cancer treatment in the last decade. This is exemplified • Characterization of role of micropeptides in by the success of checkpoint inhibitors in treating various tumorigenesis cancers. T cells mount immune response by recognizing peptide antigens presented by MHC complex on the Plasma protein biomarkers to predict cell surface. The nature of specific antigens recognized immunotherapy response in lung by T cells remains ill understood in cancers. Mutant cancers proteins that harbor cancer specific coding variations are Suitable for PhD Students. thought to be the primary source of cancer neo-antigens recognized by T cells. However, immunopeptidomics BACKGROUND: Immunotherapy has revolutionized studies have shown that the number of mutant peptides cancer treatment in the recent years. It has been from coding variations that are presented by MHC successfully used to treat several melanoma and lung complex is extremely low. Mass spectrometry based cancer patients. It is reasoned that the efficacy of immunopeptidomics studies from our lab indicates that immunotherapy in melanoma and lung cancers is due aberrant expression of proteins from non-coding regions to high mutation burden, which potentially results in high of the human genome is a major source of tumour neo- load of cancer neo-antigens on the surface that can antigens. Enhancing the expression of these proteins in be recognized by immune cells. However, not all lung cancer cells can potentially increase the load of MHC cancer patients with high mutation burden respond to class I presented neo-antigens. immunotherapy. There is a clinical need for biomarkers that can identify lung cancer patients that are most likely We are investigating potential ways to enhance the to benefit from immunotherapy. In this project, we will expression of these non-canonical proteins by cancer employ mass spectrometry based proteomics approaches cells. This strategy in combination with checkpoint to carry out plasma proteomic profiling of samples from inhibitors has the potential to augment immunotherapy lung cancer patients that undergo immunotherapy. responses in cancers. Plasma proteome profiles of patients who respond AIM: To develop novel approaches to enhance to immunotherapy and those that do not respond to expression of cancer neo-antigens and identification of immunotherapy will be compared to identify biomarkers antigens that can trigger T cell response in cancers. of response. These markers will be useful to stratify lung cancer patients that are most likely to benefit from HYPOTHESIS: Proteins encoded by non-coding immunotherapy from those that are unlikely to benefit. regions in the human genome is a major source of cancer neo-antigens. AIM: Identification of protein biomarkers in plasma to predict immunotherapy response in lung cancers APPROACHES: HYPOTHESIS: Lung cancer patients who respond to • Mass spectrometry based immunopeptidomics immunotherapy have a distinct plasma proteome profile • Transcriptomics and proteomics studies to identify compared to patients who do not respond proteins encoded by ‘non-coding’ regions in the human genome APPROACHES: • Pharmacological inhibition and siRNA based studies to • High abundant protein depletion from plasma identify targets to enhance neo-antigen production in • Fractionation of plasma proteins using HPLC cancer cells • Proteolytic digestion and sample preparation for • Assays to identify neo-antigens that trigger T cell plasma proteome profiling using mass spectrometry response • Global proteomic profiling using mass spectrometry • Animal studies to determine immunotherapy response and data analysis in vivo
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The project requires knowledge of Python or R, Medical Genomics preferably both. The project is available on an ongoing basis for Honours or Masters of Bioinformatics Group students, full time. Group Leader: Dr Nic Waddell Genome sequencing has led to great advances in cancer +61 7 3362 0101 research by identifying mechanisms of tumourigenesis, [email protected] revealing actionable mutations and profiling tumour https://www.qimrberghofer.edu.au/our- heterogeneity. To date nearly all cancer genomics has research/cancer/medical-genomics/ used short read sequencing technologies. However, short read technology is limited, as it is unable to reliably The Medical Genomics Laboratory analyses next sequence some parts of the genome or resolve complex generation sequence data to address clinical challenges structural rearrangements. Long read sequencing in a variety of diseases. overcomes these limitations and furthermore enables direct read out of DNA methylation in parallel. This project The approaches taken include: will explore the use of long read sequencing to improve • classification of samples into significant subtypes genomic characterisation of different cancer types by • identification of driver mutations analysing complex structural variants and mapping global methylation patterns. It will lead to improved • identification of mutational processes that underlie understanding of cancer biology, including development tumour development and progression as well as specific mutational Ultimately, the aim is to find alternate therapeutic targets. mechanisms. The project will use various bioinformatic These are important steps towards ‘personalised packages to analyse and present the data, but will also medicine’ where the diagnosis, management and require development of custom code. treatment of patients will be based on their individual genomic data.
Long read sequencing to extend genomic characterisation of cancer
Co-supervisors: Dr Marjan Naeini +61 7 3362 0252 [email protected]
Dr Venkateswar Addala +61 7 3845 3966 [email protected]
Dr Olga Kondrashova +61 7 3845 3966 [email protected]
QIMR Berghofer 2021 – 2022 Student Projects 27 Regulation of DNA damage repair in Complex neoantigen prediction in cancers with defective homologous cancers recombination pathway Suitable for PhD, Masters or Honours Students. The project requires knowledge of Python or R, The project requires knowledge of python or R, preferably both. The project is available on an ongoing preferably both. basis for Honours or Masters of Bioinformatics Next generation sequencing has allowed researchers to students, full time. characterise the somatic landscape of cancer genomes, Homologous recombination (HR) is an accurate DNA which has led to the discovery of biomarkers that may damage repair pathway, essential for normal cell be predictive and prognostic to targeted therapies. function. HR pathway is commonly defective in multiple However, the efficacy of current targeted therapies has cancer types including ovarian and breast cancers. It failed to raise the overall survival curve in many tumour predisposes cancer to a potent targeted therapy called types. Immunotherapy has shown a promising benefit PARP inhibitors, which has been a major improvement in treating many tumours and demonstrated remarkable for cancer care; however, treatment resistance often responses in some patients even at recurrent, relapse and develops. To tackle this resistance, a better understanding metastasis stage. The challenge now is to determine who is required of alternative DNA damage repair that takes and why some patients respond to treatment. Somatic place when HR is inactive. This project will assess the mutations within the genomes of cancer cells may result activity of alternative DNA damage repair pathways in HR in neoantigens that are presented on the tumour cell defective cancers compared with HR competent cancers surface. These can then be seen by the immune system by exploring publicly available transcriptomic, methylation and killed by the patient’s immune system. This project and genomic data, such as TCGA and ICGC. It will also will test and develop bioinformatic approaches that can explore mutational signatures and genomic scarring that be applied to understand complex tumour-immune occurs in HR defective cancers with the aim of refining interactions. Specifically the project will use genome HR signatures to identify treatment resistance. The project and RNAseq data to predict neoantigens and determine will use various bioinformatic packages to analyse and which of these be important in immunotherapy. The present the data but will also require development of findings from this work are likely to shed new insight into custom code. tumour immunology and may predict which patients will respond to immunotherapy.
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IMMUNOLOGY DEPARTMENT
Immune Targeting Translational Cancer Blood Cancers Group Immunotherapy The Immune Targeting in Blood Cancers Laboratory focuses on understanding the interplay between immunity Group and cancer cells in haematological malignancies such Team Head: as multiple myeloma, B-cell lymphoma, and leukaemia. Associate Professor Siok Tey Although immunotherapy has emerged as an important +61 7 3362 0402 treatment option, these aggressive cancers are still difficult [email protected] to cure. Using preclinical models and clinical samples, the group aims to understand how cancer cells escape https://www.qimrberghofer.edu.au/our- the immune system, and to develop new therapeutic research/cancer/translational-cancer- approaches to prevent relapse. immunotherapy/ The Translational Cancer Immunotherapy Laboratory Targeting immuno-oncology molecules studies the interaction between the immune response and in blood cancers tumour control, with a particular emphasis on translating our ever-expanding basic science knowledge into Team Head: clinically applicable therapeutic platforms. It has particular Dr Kyohei Nakamura interest and expertise in bone marrow transplantation +61 7 3845 3957 and cell and gene therapy. It is one of only a few centres [email protected] in Australia that are conducting investigator-driven clinical trials using gene-modified T cells. Can be adapted in scope for Honours or Masters. Bone marrow transplantation is arguably the most Using preclinical models and clinical samples, the project established form of cancer immunotherapy. Its curative aims to understand 1) how cancer cells escape the potential resides in the donor-derived immunity, which immune system and 2) how we can improve efficacies of can mediate a potent “graft-versus-leukaemia” immune immunotherapeutic drugs. response and eliminate otherwise incurable blood cancer. In the past decade, a number of new immunotherapeutic This project will particularly focus on understanding the approaches have emerged. One of the most exciting importance of immuno-oncology molecules that can and transformative is Chimeric Antigen Receptor (CAR) enhance immune-mediated control in acute myeloid T and NK cells, which are gene-modified immune cells leukaemia, a type of leukaemia with a poor prognosis and that have shown striking efficacy in certain types of blood few treatment options available. cancers. Our research is focused on the development In the proposed project, the student will learn the following and validation of new cellular immunotherapy strategies research techniques: 1) in vivo leukaemia models (animal that are safer, more efficacious, and have broader handling, various drug treatments, bioluminescence applicability, with the aim of translation into early imaging), 2) in vitro cell culture (gene transduction, T cell phase clinical trials. We also have a strong interest in stimulation assays, macrophage activation assays, 3) flow graft-versus-host disease, which is a common and cytometry analysis, and 4) immunoblot analysis. life-threatening immune-related complication following bone marrow transplantation. In addition to pre-clinical and clinical translational research, our group also study aspects of basic immunology that underpins and informs cellular immunotherapy, specifically the impact of viral infection and cytokine signalling on the broader immune landscape, including anti-tumour immunity and immunopathology.
QIMR Berghofer 2021 – 2022 Student Projects 29 CAR T cells – redirecting T cells for cancer immunotherapy Gordon and Jessie Suitable for Honours and PhD students. Gilmour Leukaemia Chimeric Antigen Receptors (CARs) are genetically Research Group engineered molecules that can redirect T cells to recognise particular antigens, such as those expressed by Group Leader: Associate cancer cells. T cells that are transduced by CAR targeting Professor Steven Lane CD19 have been effective in treating B cell cancers, e.g. +61 7 3362 0222 B-cell leukaemia and lymphoma, where conventional [email protected] treatments have failed. This exciting technology is one of the major breakthroughs in cancer therapy this decade https://www.qimrberghofer.edu.au/ but many challenges remain. These include cancer our-research/cancer/gordon-and-jessie- relapse due to loss of CAR T cells, antigen escape gilmour-leukaemia-research/ and other yet undefined mechanisms; life-threatening neurological toxicity and cytokine release syndrome; The Gordon and Jessie Gilmour Leukaemia Research and lack of significant success to date with CAR T cells Laboratory is researching myeloid blood cancers that targeting other cancers. This project involves developing include myeloid leukaemia (AML), myelodysplastic and testing new concepts in CAR T cell engineering to syndrome (MDS) and myeloproliferative neoplasms (MPN) improve their effectiveness, safety and applicability. as part of its translational leukaemia research work. These are very aggressive and rapidly fatal blood cancers that are among the most common types of cancer affecting Australians. The laboratory’s efforts concentrate on understanding how leukaemia stem cells in AML and MPN are able to regenerate leukaemia (or cause relapse in patients), even after cytotoxic chemotherapy. Research has focused on generating robust models of leukaemia and dissecting the pathways of self-renewal in leukaemia stem cells and normal blood stem cells.
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Characterising biomarkers of resistance Antigen Presentation and and response to standard and novel Immunoregulation therapies in Acute Myeloid Leukaemia Group Leader: Dr Kelli MacDonald Co-supervisor: Dr Claudia Bruedigam +61 7 3362 0404 [email protected] +61 7 3845 3962 [email protected] https://www.qimrberghofer.edu.au/our- research/cancer/antigen-presentation- and-immunoregulation/ Acute myeloid leukaemia (AML) is an aggressive and lethal blood cancer with a 5-year overall survival of less Globally, haematological malignancies represent the than 45% for patients younger than 60 years of age, or fifth most commonly occurring cancers and the second less than 10% for older patients. In Australia, about 1,000 leading cause of cancer death. Hematopoietic stem patients are newly diagnosed with AML each year, and cell transplantation (SCT) is the most effective curative about 60,000 new AML patients per year are estimated therapy, and the therapy of choice for the majority of for the developed world in total. Most patients initially these cancers of bone marrow origin. The curative respond to chemotherapy but ultimately relapse and die property of SCT lies in the graft-versus-leukaemia effect, from disease. Relapse is mediated by leukaemia stem which is required for ablation of residual cancer burden. cells that initiate, maintain and serially propagate AML. This process is absolutely dependent on donor T cells The development of therapeutic strategies to target contained within the graft; however, these T cells are leukaemia stem cells is therefore a promising approach also the primary mediators of graft versus host disease and key priority. (GVHD), a life threatening complication which significantly limits the success of SCT therapy. GVHD occurs in We have previously performed comprehensive, both acute (aGVHD) and chronic forms (cGVHD), which randomised, Phase II – like preclinical trials in together contribute to the significant mortality and humanised AML models treated with standard induction morbidity associated with SCT. Research undertaken chemotherapy and/or novel telomerase inhibition therapy. in the Antigen Presentation and Immunoregulation Lab Using extensive mutational and transcriptional profiling is primarily focused on using preclinical murine models techniques, we have identified molecular biomarker to dissect the immune mechanisms underpinning candidates for resistance and response to therapy. The GVHD. Driven by the increasing prevalence and severity aim of this project is to characterise biomarker candidates of cGVHD in clinical SCT patients, and the paucity of using CRISPR/Cas9 technology in AML models. This useful therapies for this disease, our research in the past project is not limited to but will involve cell culture 5 years has centred on determining the mechanistic techniques, molecular biology, immunoblotting, and flow mediators of the fibrotic manifestations of cGVHD. The cytometry. overarching goal is to identify and translate novel effective therapies, as such, our studies aim to identify targetable cellular and molecular mediators of cGVHD pathology, to confirm efficacy of targeted inhibition/promotion of these pathways in preclinical models of cGVHD and test these pathways in preclinical models of liver fibrosis to establish their broader application. Finally, targeted inhibition/ promotion of these pathways will be tested in clinical SCT patients using established national and international clinical collaborations. We have the following exciting projects that utilise novel reagents, animal models and a unique clinical sample bank, that are suitable for HDR students and have tailored projects for students entering the MD-PhD program. These projects will give students an understanding of cellular and molecular immunology with a focus on clinical translation.
QIMR Berghofer 2021 – 2022 Student Projects 31 The role of IL-17 signalling in impairment, depression and difficulty in performing monocytes and macrophages in multiple tasks simultaneously all of which adversely promoting cGVHD affect the patient’s quality of life. While the skin, lung and salivary glands are commonly effected tissues, studies Suitable for PhD or Honours Students. in both patients and mice, have demonstrated the We have identified CSF-1 and Th17/Tc17 derived IL- central nervous system (CNS) itself as a cGVHD target 17 as key cytokines that promote sequestration and organ. Although CNS GVHD is recognized, to date, differentiation of fibrogenic tissue macrophages, and the very few studies have been undertaken to identify the critical role of Ly6Clo monocyte derived macrophages, in immune mechanisms driving pathology and neurological driving cGVHD pathology. Although each represents a consequences. Our earlier studies have identified CSF-1 targetable entity, IL-17, CSF-1, TGFβ and macrophages dependent macrophages as critical mediators of cGVHD themselves all play important roles in homeostatic in multiple target organs including the skin and lung. processes including mucosal immunity and microbiome We now have preliminary data, which demonstrates diversity (IL-17), tissue remodelling (CSF-1, TGFβ) significant alterations in the brain macrophage (microglia) and tolerance (TGFβ). Thus, the ablation of any one of number and activation state with an associated decline in these modalities will likely have associated deleterious neurogenesis in transplanted mice that develop cGVHD. consequences. We therefore propose to elucidate Notably, microglial activation is broadly implicated in both how IL-17 signalling in monocytes/macrophages neuroprotection and neurodegeneration. promotes fibrogenic macrophage differentiation after In mice, neurogenesis occurs predominantly in the SCT to identify new targetable fibrogenic pathways and hippocampus and in the subventricular zone (SVZ) of the molecules evoked in these cells after SCT. This will allow lateral ventricle. The hippocampus plays important roles in the development of alternative therapeutic strategies memory, navigation and learning. Microglia play important to preferentially attenuate fibrogenic responses whilst roles in the CNS at steady state and are increasingly sparing protective homeostatic pathways. recognized to modulate hippocampal neurogenesis. HYPOTHESES: The aims of this project are to: 1. IL-17 promotes pathogenic profibrotic donor 1. Characterize the microglial populations in the macrophage differentiation after SCT. hippocampus of cGVHD vs non-GVHD mice in terms 2. Pathogenic macrophages utilise differentiation of number, morphology and transcriptome. programs that will serve as tractable therapeutic 2. Confirm the impact of CNS cGVHD on neurogenesis. targets for the treatment of cGVHD. 3. Examine the impact of CNS cGVHD on cognitive These studies will utilize our established preclinical models behaviour. of skin and lung GVHD to elucidate the direct and relative 4. Perform microglial depletion studies to confirm the contribution of IL-17 to the migration, activation, and/or direct role of microglia in altered neurogenesis and differentiation of profibrogenic monocytes/macrophages cognitive behaviour. within target organs. This is a challenging project for which the student will have a unique opportunity to undertake research across Characterisation of the effects of two fields: Transplant Immunology and Neuroscience in cGVHD on microglial function and the leading labs in both areas. Through these studies, the impact on neurogenesis and cognitive student will gain significant expertise in animal handling, function. transplant models, flow cytometry, immunohistochemistry, Supervisor: Dr Jana Vukovic (UQ) imaging and quantification, RT-qPCR and assessment of animal behaviour. Suitable for PhD or Honours Students. Chronic GVHD develops late after transplant (>100 days in patients) and presents with features that are overlapping with autoimmune diseases. Importantly, cGVHD has been shown to significantly impact neurocognitive function, which after SCT, is a serious cause of morbidity. Symptoms include memory
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Modulating donor T cell polarisation Immunopathology after bone marrow transplantation to Group prevent graft-versus-host disease Group Leader: Associate Suitable for Honours, PhD and clinical Students. Professor Kate Gartlan BACKGROUND: Donor T cell polarization is a critical +61 7 3845 3774 factor influencing the severity and tissue distribution of [email protected] graft-versus-host disease (GVHD) and the potency of graft-versus-leukaemia (GVL) effects after allo-SCT. We https://www.qimrberghofer.edu.au/our- have identified a pathogenic donor T cell differentiation research/cancer/immunopathology/ program that exacerbates GVHD without contributing The Immunopathology Laboratory is focussed on to tumour clearance, which is characterised by a unique understanding the cellular and molecular mechanisms transcription factor expression profile. that drive immune-mediated pathologies. Our recent AIMS: This study will 1) examine T cell transcription focus is on adaptive immune polarisation following factor expression after allo-SCT in both murine and allogeneic stem cell transplantation and its influence clinical samples, and 2) utilise a small molecule inhibitor on graft versus host disease (GVHD). Donor stem cell that modulates transcription factor expression to assess transplantation is an important curative therapy in the its therapeutic potential in the context of GVHD. treatment of blood cancers, however its application is limited by serious complications such as GVHD that have SIGNIFICANCE: This therapeutic approach is highly a significant impact on patient mortality and quality of life. novel and will provide the first essential proof-of-concept data to support small molecule modulation of T cell Early inflammatory responses during preparative polarisation as a method for GVHD prevention and transplant conditioning initiate a cascade of adaptive treatment. immune responses that manifest as acute and/or chronic tissue damage in >50% of transplant recipients. GVHD Characterising miRNA expression after treatment options are relatively limited and focused on immunosuppression and steroidal therapy, which are bone marrow transplantation to develop problematic due to opportunistic infection and refractory novel therapeutics disease; therefore, new therapies are urgently needed. Suitable for Honours, PhD and Clinical Students. BACKGROUND: Micro RNAs (miRNAs) are small RNA molecules (~25 nucleotides) known to play an important role in regulating inflammation and therefore may be a novel target to treat inflammatory diseases. This project will investigate the potential for miRNAs as biomarkers of disease and as novel therapeutics to modulate inflammatory responses after bone marrow/stem cell transplantation. AIMS: We are currently offering a project designed to 1) characterise miRNA expression profiles in patient serum after BMT/SCT and 2) to evaluate potential inflammatory biomarkers of GVHD. SIGNIFICANCE: New therapies are urgently needed to minimise the effects of GVHD after donor SCT/BMT. This project will use molecular and cell biology techniques and clinical samples to identify potential new targets for GVHD immunotherapy.
QIMR Berghofer 2021 – 2022 Student Projects 33 Boosting immune checkpoint regulation to prevent/limit GVHD after Inflammation allotransplantation Biology Group Suitable for Honours, PhD and clinical Students. Group Leader: BACKGROUND: Complement Receptor of the Professor Andreas Suhrbier Immunoglobulin family (CRIg) is a relatively recently +61 7 3362 0415 described molecule, which binds complement fragments [email protected] C3b, iC3b and C3c and is expressed by tissue resident https://www.qimrberghofer.edu.au/ macrophage populations. CRIg plays an important role in our-research/infectious-diseases/ hepatic clearance of complement opsonised pathogens, inflammation-biology/ and can also regulate the alternative complement activation by sequestering pathway components. GVHD The Inflammation Biology Group has developed, refined develops in >50% of leukaemia patients that receive a and characterised a number of mouse models used donor stem cell/bone marrow transplant (SCT/BMT). to gain new insights into the factors that regulate viral GVHD has a major impact on the mortality and quality-of- infection and inflammatory disease. The models are also life for these cancer survivors, however treatment options exploited for collaborative research and development with are very limited and steroid refractory GVHD patients industry to test potential new interventions (e.g. vaccines, (~20%) have particularly high mortality rates. Complement anti-inflammatory drugs, anti-viral agents). activation is known to contribute to GVHD, whereby The group has over 25 years of activity in improving complement deficient mice are protected from lethal our understanding of the immunopathogenesis of the GVHD after allogeneic SCT. Therefore, CRIg may be a diseases cause by arthritogenic alphaviruses such as novel target to treat inflammatory diseases such as graft- chikungunya virus and Ross River virus. We have also versus-host disease (GVHD). developed mouse models of Zika virus (foetal brain AIMS: 1) Characterise CRIg expression in GVHD target infection and testes damage) and Yellow fever virus liver organ tissue after syngeneic BMT/SCT and allogeneic pathology, which have been used in the development BMT/SCT. 2) Characterise the effects of novel immune of vaccines and characterisation of pathogenic checkpoint ligand therapy on T cell responses in vitro. 3) determinants. Establish the therapeutic effects of immune checkpoint Very recently, we repurposed a PC3 laboratory and have ligand therapy in vivo following allo-SCT. started to undertake research into SARS-CoV-2 and COVID-19 using transgenic hACE2 mice.
Sorting out the granzyme A and Nnt mess
Co-supervisor: Dr Daniel Rawle +61 7 3845 3733 [email protected]
Suitable for PhD Students only. We have recently discovered that the literature on granzyme A (GzmA) is badly compromised by the use of GzmA-/- mice, which have a full length Nicotinamide Nucleotide Transhydrogenase (Nnt) gene, whereas the control C57BL/6J mice have a truncated Nnt gene. We have now generated a new GzmA mutant mice (GzmAS211A) on a pure C57BL/6J background, to begin again the quest for understanding what this abundant, circulating, proteolytically active enzyme secreted by
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cytotoxic lymphocytes actually does. Historical studies argue that GzmA is involved in delivering cell death and/ Translational and or promoting inflammation, with GzmA reported to be involved in a large range of settings including cancer Human Immunology and infectious diseases. The Nnt problem appears to also have contaminated a large body of work with ≈27% Group of NCBI Run Accessions and ≈38% of Bioprojects Group Leader: incorrectly listing C57BL/6J as the mouse strain (https:// Associate Professor www.biorxiv.org/content/10.1101/2021.03.16.435730v1. Corey Smith abstract). Nnt controls reactive oxygen species and +61 7 3362 0313 therefore influences a large range of cellular activities. We [email protected] have thus generated matched Nnt+ and Nnt- mice, to unravel exactly how this large body of literature may have https://www.qimrberghofer.edu.au/our- been compromised by the presence of this gene. The research/infectious-diseases/translational- and-human-immunology/ project will involve a range of mouse models of cancer and viral infections, as well as RNA-Seq and will be The major focus of the Translational and Human supported by a team of virologists and bioinformaticians. Immunology group is to delineate the mechanisms that regulate human immune responses in health and Testing new interventions against disease. Knowledge gained from these studies forms SARS-CoV-2/COVID-19 using mouse the basis for developing novel immune interventional and models diagnostic strategies that can be implemented in clinical settings. The group is also interested in understanding Suitable for PhD Students only. the transcriptional and epigenetic regulation of human The severe acute respiratory syndrome coronavirus 2 immune responses during persistent viral infections (SARS-CoV-2) pandemic has sparked an unprecedented and human cancers, and in developing strategies to global quest for vaccines and treatments. Key to such manipulate this regulation to improve outcomes following efforts are animal models of SARS-CoV-2 infection and immune intervention. COVID-19 disease. We have recently refurbished a state- of-the-art PC3 facility at QIMR Berghofer MRI for SARS- COVID-19 immunity – Identifying CoV-2 research and have established a number of mouse memory T cell protection against models that express the human Angiotensin-Converting Enzyme 2 (hACE2), the primary cellular receptor for SARS-CoV-2 SARS-CoV-2. The project will involve characterization of the virological and immunological parameters and Co-supervisor: mechanisms underpinning virus replication and disease Dr Katie Lineburg in the different mouse models and for the different +61 7 3362 0386 strains of SARS-CoV-2. The project will involve animal [email protected] handling, virological assays and RNA-Seq and will be supported by a team of virologists and bioinformaticians. Suitable for Honours or Masters Students. We also envisage involvement in the evaluation of new interventions developed by our collaborators (e.g. The recent COVID-19 pandemic has demonstrated how https://pubmed.ncbi.nlm.nih.gov/33811809/). A highly susceptible the global population is to newly emerging dedicated, calm and careful individual is sought, given diseases. Equally, recent months have demonstrated the complex PC3 safety protocols and the high risk how advanced scientific knowledge can be translated associated with working with this highly infectious virus. into the rapid development of new treatments to combat QIMR Berghofer requires and arranges that all staff emerging pathogens. working in the facility be vaccinated.
QIMR Berghofer 2021 – 2022 Student Projects 35 Our research group is a part of the Centre for Vaccine and Immunotherapy Development, located at QIMR Tumour Immunology Berghofer Medical Research Institute. We have a strong focus on studying the white blood cells responsible for Group targeting and killing diseased cells in the body, the T cells. Group Leader: In particular, we focus on identifying virus-associated T Professor Rajiv Khanna cell responses in disease and engineering T cell based +61 7 3362 0385 immunotherapies to treat a range of malignancies. Our [email protected] most recent clinical study, published in the Journal of Clinical Investigation, examined patient immune https://www.qimrberghofer.edu.au/our- responses following T-cell immunotherapy to treat the research/cancer/tumour-immunology/ primary brain cancer Glioblastoma. The major goal of the Tumour Immunology Laboratory Recently our group have established a strong COVID-19 is to obtain a deeper understanding of the mechanisms research program that is aimed at investigating the T cell by which an immune response to tumours may be immune response to SARS-CoV-2 infection. In 2020, we generated, augmented and applied to the inhibition of developed a rapid monitoring assay for the detection of tumour growth. The members of this laboratory share SARS-CoV-2 T cell responses and used this to identify the expectation that such insight will be applicable to the which SARS-CoV-2 proteins drove dominant T cell treatment and/or prevention of cancer. responses in recovering patients. Adoptive T-cell therapy for HPV From here we have continued to investigate these associated cancers dominant SARS-CoV-2 T cell responses and in 2021 the journal Immunity published our discovery that cross- Co-supervisor: recognition between coronavirus variants is actually Dr Kunal Bhatt quite limited. We identified that T cells can indeed cross- +61 7 3362 0386 recognise different virus variants but that this ability is [email protected] actually quite rare and heavily dependent upon where the mutation falls within the genetic sequence of the virus. Suitable for PhD or Honours Students. Our COVID-19 research program is now seeking interested students to take part in a study investigating Long-lasting infections with high-risk human papillomavirus the long-term immune memory protection associated -16 (HPV16) can cause epithelial cancers, which include with SARS-CoV-2. We intend to examine T cell immunity squamous cell carcinomas (SCC) and adenocarcinomas against SARS-CoV-2 and have the potential to investigate of the cervix, oropharynx, anus, vulva, vagina, and this in response to both natural infection and vaccination penis. Oncogenic HPV virus accounts for approximately settings. The appropriate student will assist us to extend 600,000 cases worldwide every year and advanced HPV- our understanding of the dominant SARS-CoV-2 immune associated cancers are generally incurable and resistant responses within the Australian population and to explore to chemotherapy. However T cell receptor (TCR)-based the effectiveness of current vaccination programs to adoptive T cell therapies (ACT) hold great promise for establish effective long-term T cell immune protection. the treatment of HPV associated cancer, targeting viral antigens which are absent in healthy tissues, making them The study will provide students with experience in attractive targets for genetically engineered T-cell therapy. molecular and cell biology techniques including cell We have been working on the samples of oropharyngeal phenotyping using flow cytometry, gene expression cancer patients and identified HPV16 antigens specific analysis using NanoString technology and the potential high-avidity CD4+ and CD8+ TCRs directed against for computational analysis where student undergraduate different HPV16 antigens by single cell TCR sequencing. training is appropriate. Currently the project is working on: AIM 1- Functional characterisation of HPV specific transgenic TCR T cells, which involved assessing the in vivo efficacy by real time killing assay (Xcelligence assay) and flow cytometry and ex vivo efficacy using HPV xenograft mice model.
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AIM 2- Adoptive therapy with ex vivo–expanded genetically modified antigen-specific T cells, which can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. This focuses on the use of different cytokines and metabolic checkpoint inhibitor or epigenetic regulator in ex vivo culture to further enhance the efficacy and quality of genetically modified HPV-specific T cells. This project involves characterisation of HPV16 specific transgenic TCR T cells and standardisation of culture conditions to further improve their effectiveness and applicability.
Improving the efficacy of T-cell therapy in vivo
Co-supervisor: Dr Debottam Sinha +61 7 3362 0386 [email protected]
Suitable for Masters or Short-term clinical Students. Adoptive T-cell therapy (ACT) has shown good promise in the treatment of a range of virus-associated diseases and haematological cancers. However, it faces a number of barriers to efficacy against solid cancers, as the tumour microenvironment (TME) and disease burden play a critical role in regulating the clinical outcome of ACT. Cancer-intrinsic pathways alongside tumour heterogeneity dictate the hostility of the TME, enable immune escape, and facilitate adaptive resistance to ACT. These pathways involve receptor tyrosine kinase, anti-apoptosis, cancer metabolism, epigenetic and cell cycle pathways, which are the hallmarks of tumour progression and survival. We postulate that cancer-intrinsic pathways heavily contribute towards compromising anti-tumour immune responses and promote network rewiring that enables adaptive resistance against ACT. Therefore, molecular targeting of these pathways in combination with ACT forms a rational approach for the treatment of aggressive solid cancers. This project will delineate the functional role of multiple cancer-intrinsic pathways in augmenting resistance to ACT, using a platform developed by our laboratory against Epstein–Barr virus (EBV)-associated solid cancers. In addition, the project will characterise the synergism of novel therapeutic strategies that include the combination of EBV-specific ACT and targeted therapy against cancer intrinsic pathways using small molecule inhibitors.
QIMR Berghofer 2021 – 2022 Student Projects 37 CELL & MOLECULAR BIOLOGY DEPARTMENT
The innovative aspect of this project comprises of Cellular immunotherapy – engineering the strategically targeting cancer-intrinsic pathways “custom built” cells to treat cancer regulated by the EBV-associated latent genes using the respective small molecule inhibitors (SMI) to enhance Co-supervisor: the efficacy of T-cell therapy against solid cancers in Dr Paolo Martins the clinic. Importantly, these pathways are known to +61 7 3845 3801 facilitate network rewiring upon challenge with anti- [email protected] cancer therapeutics; hence characterizing their function in supplementing resistance against T-cell therapy is of high significance. As a stand-alone, SMIs used for This project is suited for a Master’s or PhD work and is targeted therapy have shown low response rates with flexible for clinical students. poor clinical outcome. The project will emphasize the Current standard approaches for the treatment of human concept of “repurposing” the use of SMIs to overcome cancers typically employ broad acting radiotherapeutic a hostile TME and overcome cancer-imposed resistance and chemotherapeutic approaches. There has been as a rationale of combining with ACT. The creativity of this growing interest in approaches using immunotherapy project stems from broadening the clinical applicability with adoptive cell transfer (ACT): using patient’s immune of SMI to enhance immune cell function and sensitize cells to treat their cancer. A specific type of ACT a hostile TME to a favourable TME, by overcoming uses chimeric antigen receptors (CARs). These are adaptive resistance; hence endorsing the rationale genetically engineered molecules, which are custom of formulating novel molecular-cellular therapies. The built to specifically target protein antigens expressed on study will enable student to gain expertise in performing malignant cells. There are three FDA-approved CAR T molecular techniques involving gene cloning, cell survival cell-based therapies targeting CD19 on certain B-cell and killing assays, flow cytometry, immunofluorescence, malignancies. CAR19 treatment, of children with relapsed and immunohistochemistry to generate in vitro data. It will or refractory acute lymphoblastic leukaemia (ALL), and also provide the opportunity to learn use of in vivo murine of adults with advanced lymphomas, has demonstrated xenograft models to test the efficacy of the combination remarkable success and complete remission in some strategy, which in future might lead to a possible patients. Although approved therapies are limited to blood manuscript to be submitted in a highly reputed journal. cancers, a growing number of CAR T-cell therapies are being developed and tested in clinical studies in multiple solid tumours. There are promising clinical data targeting tumour-associated antigens in melanoma, lung, liver, breast, and brain cancers. There are major differences between CAR therapies, mostly at the tumour-antigen recognition site, but CARs share similar components known as signalling domains that can affect the cells’ overall function, such as their ability to produce more cells after infusion into the patient (expansion), and to survive longer in circulation (persistence). The ability to manipulate these domains to custom build CAR T cells to specifically target certain tumours, and avoid toxicity, is critical for the success of CAR T cell therapy.
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The CAR T cell program at the Tumour Immunology Laboratory aims to design and test novel CAR T cell Drug Discovery Group therapies for virus-associated cancers. We have designed a CAR T cell, which targets a glioblastoma (GBM) Group Leader: -specific antigen A3 that is being tested for the treatment Professor Peter Parsons of GBM, an aggressive form of brain cancer. In our clinical +61 7 3362 0316 trial of ACT to treat GBM (1) we identified a distinct T [email protected] cell expression signature associated with potency and https://www.qimrberghofer.edu.au/our- favourable long-term survival in GBM patients. This research/cancer/drug-discovery/ project will use this knowledge and expand the potential of the A3-specific CAR T cell product. We will customise The Drug Discovery Group combines expertise in cancer the signalling domains to engineer a CAR with a similar biology with drug discovery. expression signature to that of T cells with known GBM- Our drug discovery focuses on two areas: killing potential. We will ultimately build a CAR better suited for the treatment of GBM. 1. The chemistry and manufacturing aspects of the novel anticancer drug, EBC-46. This includes devising and The student will learn in vitro molecular and cell biology testing a satisfactory formulation for formal toxicology, techniques involving gene cloning, non-viral transfections, prior to clinical trial. lentiviral transductions, cell phenotyping using flow cytometry and NanoString technology. For a PhD student 2. Development of suitable assays for primary screening the work will also involve in vivo study in murine xenograft of a rain forest plant extract library, looking for models of GBM to test the efficacy of the custom-built anticancer and anti-inflammatory activities. CAR T cells. This laboratory has access to: • a unique library of natural products from the rainforest of Northern Australia, some with potential for treatment of various types of cancer • a selected set of human tumour cell lines for discovery and evaluation of new anti-cancer agents • functional biological assays to determine efficacy of novel compounds for anti-cancer, anti-inflammatory and antibiotic activities. Our cancer biology work currently focuses on understanding the development and progression of cancers of the skin and oral cavity. Specifically, we are investigating the molecular mechanisms involved in the progression and metastasis of melanoma, head and neck cancer, as well as cutaneous squamous cell carcinoma. The identification and understanding of aberrantly regulated pathways in these cancers is crucial prior to the design or identification of suitable agents to treat the diseases. Our research programs are synergistic and complementary.
QIMR Berghofer 2021 – 2022 Student Projects 39 Investigating the anti-cancer activity of the Epoxytigliane family. Epigenetics and
Supervisor: Disease Group Dr Jason Cullen Determining the therapeutic efficacy of +61 7 3845 3741 epigenetic drugs in ovarian cancer [email protected] Team Head: Previous work performed by the Drug Discovery Group, Associate Professor Jason Lee together with QBiotics Ltd. (an Australian based biotech +61 7 3845 3951 company situated in North Queensland), has led to [email protected] the identification of a family of natural products (the Epoxytigliane family) with significant anti-cancer potential. https://www.qimrberghofer.edu.au/our- Intratumoural injection of the prototypical member of research/cancer/epigenetics-and-disease/ this family, tigilanol tiglate (also known as TT or EBC-46), gives long-term ablation, approaching cure, of cutaneous Co-supervisor: tumours in dogs, cats and horses. We have also shown Dr Francesco Casciello at QIMR Berghofer that intratumoral injection of TT +61 7 3845 3980 ablates subcutaneous tumours in several mouse models [email protected] of cancer, with few recurrences. Localized haemorrhagic necrosis appears to be the overt mechanism of efficacy in Because cancer and many diseases arise from a vivo, occurring primarily as a result of vascular disruption combination of genetic propensity and the response of at the lesion site, followed by tumour cell necrosis. cells to external factors mediated through changes to the expression of key genes, it is important to understand Our recent data suggest that TT can also induce a form epigenetic regulation. The epigenome is crucial to the of cellular demise in tumour cells known as ‘immunogenic changes of gene expression and there is now strong cell death’ (ICD). ICD has the potential to augment evidence that epigenetic alterations are key drivers of systemic immune responses to tumours, in addition to cancer progression. However, very few drugs targeting improving patient response to other immunotherapeutics epigenetic modifiers have been successful, in part due to e.g. immune checkpoint inhibitors. The overall goal of the the lack of effective means to select the patient group in proposed project is to investigate the potential of additional which they will be most effective. This highlights an urgent epoxytigliane family members to induce anti-tumour need to understand the molecular basis of epigenetic immunity, whether they can provide improved responses changes in aggressive cancer. Therefore, understanding compared to TT and the mechanisms by how this occurs. the role of these enzymes in cancer progression using AIMS: patient-derived samples will aid in improving existing • To investigate the ability of several epoxytigliane family therapies and potentially identify new targets for members to induce facets of ICD. treatment. • To determine the ability of these compounds to induce HYPOTHESIS anti-tumour immune responses in several mouse 1. Deregulation of epigenetic modifiers is responsible for models of cancer. cancer progression and metastasis, • To investigate combinations of family members with other therapeutics of interest. 2. Inhibiting the activity of epigenetic modifiers will allow re-expression of genes that may improve outcome of EXPERIMENTAL TECHNIQUES AND cancer patients. APPROACHES: • Cell culture and manipulation of tumour cell lines. • The use of microscopy, flow cytometry, ELISA and immunoblotting approaches. • Potential RNAseq analysis of tumours. • Use of mouse models of cancer and associated imaging technology.
40 QIMR Berghofer 2021 – 2022 Student Projects CANCER PROGRAM
AIM AIM The overall goal of this study is to develop a novel The aim of this study is to develop a combined therapy targeting epigenetic modifiers and validate the therapy using epigenetic modifier inhibitors and epigenetically-suppressed gene signature that predicts immunotherapeutic agents in vivo for the treatment of outcome in aggressive cancer patient samples to patients at high risk of recurrence and metastasis. generate a signature-based diagnostic tool that can APPROACHES identify cancer patients at high risk of recurrence and metastasis. 1. Cellular models and treatments APPROACHES 2. Characterisation of the epigenetic modifier change by RNA-seq 1. Cellular models and treatments 3. In vivo mouse model of melanoma 2. Characterisation of the epigenetic modifier change by RNA-seq 4. Protein complex purification and proteomics 3. Promoter methylation analysis 5. Characterisation of putative target genes by ChIP-seq 4. Protein complex purification and proteomics Therapeutic opportunities targeting epigenetic- metabolism crosstalks in cancer 5. Immunoprecipitation assays Epigenetic and metabolic pathways in cancer cells 6. Characterisation of putative target genes by ChIP-seq are highly interconnected. Epigenetic landscape in cancer cells is modified by oncogene-driven metabolic Combining epigenetic drugs with changes. Metabolites modulate the activities of epigenetic immunotherapy in melanoma modifying enzymes to regulate the expression of specific Whereas advances in immune and targeted therapies genes. Conversely, epigenetic deregulation that occurs in have made tremendous progress recently they are cancer affect the expression of metabolic genes, thereby effective only in distinct subsets of patients or result in altering the metabolome. These changes all co-ordinately the emergence of drug resistance. In addition, prohibitive enhance cancer cell proliferation, metastasis and therapy cost of immunotherapy can be overcome by therapy that resistance. This project aims to understand the link uses relatively inexpensive small molecules. Patients suffer between the activity of epigenetic modifying enzymes considerable side effects and these may be alleviated and the expression of metabolic genes. We anticipate by changed drug doses when used in combination with that this project would lead to unravelling novel molecular other drugs. Thus, investigation of alternative approaches targets, whose intervention may lead to improvements is essential. Recent studies have shed light on the in cancer treatment. In this project, we will examine importance of epigenetic regulation in cancer biology metabolic pathways that are dysregulated in cancer and including overexpression of histone methyltransferases in identify promising molecular targets, with an approach to cancers. Combining inhibitors of epigenetic modifiers may utilise small molecule or biologic inhibitors against these either enhance the efficacy of immunotherapy or treat abnormalities. The techniques employed will include those patients that have become resistant to therapy. molecular biology (protein, RNA and DNA), transcriptomic analysis, single cell imaging, metabolite analysis and HYPOTHESIS proteomics. Combining epigenetic modifier inhibitors with immunotherapy will be more effective compared to using one drug alone.
QIMR Berghofer 2021 – 2022 Student Projects 41 Colorectal Cancer – from Genetics Conjoint to Chemoprevention Gastroenterology Supervisor: Associate Professor Vicki Whitehall Group This project will use a well-developed in vivo model to investigate the role of various drugs in the prevention Honorary Group Leader: of bowel cancer. Using an inducible BRAF mutant Associate Professor mouse, we have observed the sequential development Vicki Whitehall of intestinal hyperplasia, polyps and ultimately advanced cancer, in a model that closely mimics human serrated +61 7 3362 0170 neoplasia. This project will investigate therapeutic [email protected] intervention to reduce the incidence of polyps and https://www.qimrberghofer.edu. prevent cancer. Molecular studies using techniques such au/our-research/cancer/conjoint- as mutation detection, DNA methylation, expression gastroenterology/ microarrays and immunohistochemistry will also be The Conjoint Gastroenterology Laboratory studies utilised to study the effects of the interventions. the molecular genetic alterations, which underlie the This project would suit a highly motivated student with an progression of benign bowel polyps to bowel cancer. It interest in colorectal cancer genetics and therapy, who has a particular interest in serrated polyps, which were enjoys working individually and as part of a team. previously thought to have no malignant potential but are now recognised to be the precursors of approximately Genetic changes underlying colorectal 20% of bowel cancers. This work has led to profound cancer initiation and progression changes in the practice of colonoscopy so that it now better protects against bowel cancer. The laboratory Supervisor: Associate Professor Vicki Whitehall has now developed an animal model of the serrated pathway and are testing chemoprevention strategies. Suitable for PhD and Honours students. The bowel cancers, which arise through the serrated In the Conjoint Gastroenterology Laboratory, we pathway often, carry an oncogenic BRAF mutation and are interested in characterising the genetic changes develop DNA methylation silencing important genes underlying the progression of pre-cancerous colonic such as mismatch repair genes. These characteristics polyps to colon cancer. We work closely with clinicians are important in predicting prognosis and response to specialising in Gastroenterology, Pathology, Oncology and chemotherapy and this is also a focus of our research Genetics to increase our understanding of this disease programme. Collaboration with gastroenterologists, and improve patient management and outcomes. surgeons, pathologists and oncologists is a key aspect of Potential projects will examine candidate genes for a role its research. in the development of colorectal cancer, selected from bioinformatic analysis of genome-wide data including expression arrays, DNA methylation array profiling and next generation genomic sequencing. Candidate genes will be examined in a clinically and molecularly well-defined series of colorectal polyps and cancers. Functional studies will be conducted in colorectal cancer cell lines and in xenograft models. Projects are also available to examine strategies for pharmacoprevention using our BRAF mutant murine model.
42 QIMR Berghofer 2021 – 2022 Student Projects Enhancing the efficacy of conventional Translational Cancer immunotherapies Discovery Group Some components of this project are suitable for Honours students, flexible for Medical/clinical students Group Leader: and entire project is suitable for PhD students. Dr Bill Dougall Members of the Translational Cancer Discovery Group Phone: +61 7 3845 3506 were involved in the original development of denosumab, Email: [email protected] a monoclonal antibody against RANKL, which is now approved worldwide for the treatment of bone metastasis Honours, Master, Clinical and PhD students are and multiple myeloma. Recent research by the lab using welcomed to express their interest. preclinial models has demonstrated that antibodies against RANKL improve the anti-tumour efficacy of Cancer is one of the most deadly diseases accounting for conventional immunotherapies, such as anti-PD-1/PD- nearly 10 million deaths worldwide in 2020, highlighting a L1 or anti-CTLA4 antibodies. This increased efficacy is crucial need to develop innovative therapeutics to improve associated with increased anti-tumour immunity, however, the survival of cancer patients. The advent of antibody- the precise mechanism and cellular target regulated by based therapies has revolutionized cancer treatment, the RANK(L) pathway are unknown. allowing for very precise targeting of the tumour cells themselves (e.g. Herceptin for certain breast cancers) These data have rationalised a novel clinical trial of or immunotherapy approaches, in which “checkpoint Pre-operative evaluation of anti-PD-1 checkpoint inhibitor” antibodies very specifically target immune inhibition (nivolumab) combined with RANKL blockade proteins and boosts the body's natural defenses to fight (denosumab) in stage IB-IIIA non-small cell lung cancer cancer. (NSCLC) patients (POPCORN trial). We now wish to use mouse tumour models and clinical trial samples The Translational Cancer Discovery Group is particularly to determine the precise mechanism by which RANKL interested in engineering novel antibody-based cancer inhibition enhances immunotherapy. In addition, utilisation therapies that can directly target certain tumour cells and, of transcriptomics and multiplex IHC applied to clinically simultaneously, also targets key immune cell proteins, annotated cohorts of CRC, NSCLC and melanoma therefore combining two cancer therapy approaches in samples will allow an interrogation of the functional status one drug. We are validating these drug candidates using of specific immune cells in relationship to RANKL and genetically-engineered mouse models of cancer along potential relationship to immunotherapy response. This with state-of-the art flow cytometry and other tissue is a prime example of the “reverse translation” paradigm, imaging platforms. in which clinical trial samples and results will inform Importantly, our approach to cancer drug development mechanistic, pre-clinical studies. The trainee will learn and is informed by the “reverse translational research” use recently-developed translational approaches to the paradigm. This means that we utilise cutting-edge clinical trial samples (eg flow cytometry, transcriptomic translational experiments using patient-derived materials analysis and mutliplexed immunohistochemistry) and/or from on-going cancer clinical trials to help understand experimental mouse models of cancer. mechanisms and design the next generation of cancer therapies. Currently, we are engaged in clinical trial activities that include experimental treatments for patients with non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer and breast cancer.
QIMR Berghofer 2021 – 2022 Student Projects 43 Development of new bi-functional Role for specialised lymph node cells in antibodies for the treatment of Head cancer immunity and Neck Squamous Carcinoma Some components of this project are suitable for (HNSCC) Honours students, flexible for Medical/clinical students This project is flexible for Honours students, Masters and entire project is suitable for PhD students. students or Medical/clinical students. Immunotherapies, particularly immune checkpoint Head and neck squamous cell cancer (HNSCC) is the inhibitors, will likely become the treatment backbone for eighth most common cancer diagnosed in Australia, the majority of cancer patients over the next 10 years with over 1000 deaths from advanced disease each given the paradigm improvement in overall survival in year. For survivors, toxicity related to treatment of responsive patients. However, many patients do not primary and nodal spread in the mouth and/or neck respond or acquire resistance. A better mechanistic (surgery, radiotherapy, chemotherapy) can be morbid and understanding of checkpoint inhibitors is needed to protracted. There is accumulating evidence indicating the improve cancer patient response to immunotherapies. immunomodulatory effects of HNSCC by which it can Originally, the immune checkpoint PD-1/PD-L1 blocking escape and/or suppress the immune system, however antibodies were thought to act primarily within the local much is still unknown about the different mechanisms of tumour microenvironment by re-invigorating T-cells and immune suppression in HNSCC. thereby revive existing anti-tumour immunity. However, an emerging hypothesis indicates a key role for systemic We have an ongoing clinical trial of HNSCC in which immune cells of the lymph node in the response of we obtain tumour samples that enable “multi-omic” patients to checkpoint inhibitors. analysis of the immune microenvironment of HNSCC and functional testing of novel bi-functional antibodies. Our group is particularly interested in two specialised The Flow Cytometry facility at QIMR Berghofer enables compartments of the lymph node: the lymphatic a very broad analysis of different immune cells present endothelial cell (LEC) and the subcapsular sinus in HNSCC tumours, which can ultimately be related macrophage (SSM). Both cells play a key role in the to the patient’s prognosis. Candidate cell-types that generation of adaptive immune responses, transporting may contribute to HNSCC immune evasion include antigen and antigen-presenting cells (APCs) from certain dendritic cells and myeloid-derived suppressor peripheral tissues to lymph nodes during normal immune cells (MDSC). Different ligands expressed by HNSCC responses. However, whether these cells play critical tumours may stimulate dendritic cells or MDSC, roles in anti-tumour immunity is largely unexplored. leading to immunosuppressive effects by reducing Our approach is to utilize flow cytometry and RNA T-cell function. For functional drug testing of novel bi- sequencing to study immune changes in the tumour- functional antibodies, we are particularly interested in draining lymph node with and without treatment with antibodies, which block multiple different tumour ligands checkpoint inhibitors (eg anti-PD-1 antibodies) or anti- simultaneously and therefore reduce immunosuppressive RANKL antibodies in preclinical tumour models. We have effects. also generated genetically modified mice in which the In the proposed project, the student will learn: 1) RANKL signaling pathway is deleted specifically in LEC or high-content flow cytometry of each of the relevant SSM cells, which would allow a precise mechanistic study immune cells present in HNSCC; 2) In vitro techniques in the context of tumour immunity. Importantly, we would demonstrating immune-suppressive effects of HNSCC use multi-plexed immunohistochemistry to translate the co-cultured with dendritic cells, MDSC, T-cells; 3) In vitro observations from the preclinical models into an analysis drug testing, using novel bi-functional antibodies. of tumour-associated lymph nodes obtained from human cancer patients. In this project, the student would learn how to plan and conduct animal cancer models, multi-colour flow cytometry, RNA-sequencing and bioinformatics, and multi-plexed immunohistochemistry.
44 QIMR Berghofer 2021 – 2022 Student Projects Infectious Diseases Program The COVID-19 pandemic highlights the devastating impact infectious disease can have on human health and society.
Around 400,000 Australians are hospitalised each Types of infectious diseases studied: year with infections. Sadly, infectious diseases • Epstein-Barr virus (EBV) • Mosquito-borne viruses disproportionately effects our first Australians and people living in the developing world, especially young children. • Glandular fever • Rheumatic fever and rheumatic heart disease The Infectious Diseases Program at QIMR Berghofer • HIV and AIDS works to develop drugs, vaccines, and prevention and • Scabies education strategies against globally important diseases • Hydatid disease • Schistosomiasis (blood caused by parasites, bacteria and viruses. • Intestinal worms flukes) Our specialist labs have an international reputation in • Leishmaniasis malaria volunteer infection studies and test new anti- • Streptococcal-related malaria drugs for deployment in the developing world. • Malaria infections (toxic shock syndrome, necrotising We have a distinguished history studying viruses and use fasciitis, scarlet fever, this knowledge to develop new treatments, as well as impetigo, strep throat) cellular therapies for cancer and disease of the central nervous system. We have a strong record in vector control and work on innovations in mosquito surveillance and measures to interrupt pathogen transmission, and deliver a strong helminth control program resulting in major public health gains. Our dedicated scabies lab researches this neglected disease that excessively affects our indigenous population.
QIMR Berghofer 2021 – 2022 Student Projects 45 CELLULAR & MOLECULAR BIOLOGY DEPARTMENT IMMUNOLOGY DEPARTMENT
activity assays. SjAChE knocked-down schistosomula will Molecular then be used to infect mice. At six-weeks, post-challenge infection the mice will be perfused and adult worms will Parasitology Group be counted and used for further phenotypic studies. The Group Leader: establishment of a CRISPR-Cas9 system in schistosomes Professor Don McManus will significantly improve the ability to manipulate the schistosome genome; and will help in the identification +61 7 3362 0401 of new drug/vaccine targets and the unravelling of drug [email protected] resistance mechanisms. https://www.qimrberghofer.edu.au/our- research/infectious-diseases/molecular- Development of new interventions parasitology/ including vaccines, DNA diagnostics The Molecular Parasitology Laboratory researches and serological markers essential for the biology and epidemiology of parasitic worms of ending neglected tropical diseases humans and works on developing new interventions and caused by schistosomes and intestinal diagnostic procedures that will lead to their elimination. worms in Asia and Africa. The lab researches parasitic worms of humans, Suitable for PhD or Honours students. particularly schistosome blood flukes, which are responsible for the potentially debilitating disease The Neglected Tropical Diseases (NTDs) are a group schistosomiasis (Bilharzia), and dog tapeworms of parasitic/bacterial diseases that cause substantial (Echinococcus), which are the cause of hydatid disease. morbidity for more than one billion people globally. Affecting the world’s poorest people, NTDs cause severe Establishment of a CRISPR-Case9- disability, hinder growth, productivity and cognitive mediated gene knock-down system in development, and often end in death; children are Schistosoma japonicum targeting the disproportionately affected. Asia is a NTD hot spot acetylcholinesterase gene claiming some of the highest infection rates in the world, second only to that of sub-Saharan Africa. Approximately Suitable for PhD or Honours students. one-third of the world’s parasitic worm infestations occur Schistosomiasis is a serious global problem and the in this region. Our laboratory focuses on understanding second most devastating parasitic disease following the biology and epidemiology of NTDs caused by malaria. Currently, there is no effective vaccine available parasitic worm infections due to the Schistosoma blood and treatment is entirely dependent on praziquantel flukes (schistosomiasis), the Echinococcus (hydatid) chemotherapy, raising a significant threat to public health. tapeworms (echinococcosis) and soil transmitted The paucity of molecular tools to manipulate schistosome helminthiases – diseases of the world’s poorest people gene expression has made an understanding of genetic that result in both major suffering and economic loss. pathways in these parasites difficult, increasing the Our laboratory has research projects suitable for PhD challenge of identifying new potential drug/vaccine study in: candidates. • Schistosomiasis epidemiology, surveillance and In this project, we aim to establish a CRISPR (clustered response with a focus in China. regularly interspaced short palindromic repeat)-Cas9- • Schistosomiasis vaccine development/deployment. mediated gene knock-down system in Schistosoma japonicum. The CRISPR/Cas9 system allows cell • Epidemiological studies and research to eliminate genomes to be edited at targeted locations using the echinococcosis in China through integrated control Streptococcus pyogenes Cas9 nuclease (SpCas9) approaches. under the guide of a single-guide RNA (sgRNA). Cas9- • “Magic Glasses” Asia: Testing a video-based health gRNAs targeting on gene-acetylcholinesterase (AChE) educational intervention package for its impact on will be delivered into the schistosomule larval stage of S. intestinal parasitic worm incidence, knowledge and japonicum by electroporation to induce gene mutation hygiene behaviour in primary school children in Asia. in a model locus. To test CRISPR/Cas9-mediated gene knock-down in S. japonicum schistosomula, we will target This research is supported by project and program grant SjAChE and assess the degree of AChE loss using AChE funding from the National Health and Medical Research
46 QIMR Berghofer 2021 – 2022 Student Projects INFECTIOUS DISEASES PROGRAM
Council of Australia, UBS Optimus Foundation of Switzerland, The Australian Infectious Disease Centre and Immunology and the Chinese Government. Infection Group New interventions to end neglected Group Leader: tropical diseases in Asia. Professor Christian Engwerda Suitable for PhD or Honours students. +61 7 3362 0428 [email protected] The Neglected Tropical Diseases (NTDs) are a group of parasitic/bacterial diseases that cause substantial https://www.qimrberghofer.edu.au/our- morbidity for more than one billion people globally. research/infectious-diseases/immunology- Affecting the world’s poorest people, NTDs cause severe and-infection/ disability, hinder growth, productivity and cognitive The Immunology and Infection Laboratory studies host development, and often end in death; children are immune responses during malaria and leishmaniasis. Its disproportionately affected. Asia is a NTD hot spot aim is to distinguish anti-parasitic host immune responses claiming some of the highest infection rates in the world, that control infection from those that cause disease. second only to that of sub-Saharan Africa. Approximately The laboratory uses experimental models, as well as one-third of the world’s parasitic worm infestations occur samples from patients and human volunteers deliberately in this region. Our laboratory focuses on understanding infected with parasites for their research. Particular the biology and epidemiology of NTDs caused by interest is on understanding how T cells influence anti- parasitic worm infections due to the Schistosoma blood parasitic immune responses. flukes (schistosomiasis), the Echinococcus (hydatid) tapeworms (echinococcosis) and soil transmitted The long-term goal of research is to develop better helminthiases – diseases of the world’s poorest people vaccines and therapies to prevent and treat infectious that result in both major suffering and economic loss. diseases. Our laboratory has research projects suitable for PhD study in: Discovering novel immunoregulatory molecules that can be manipulated for • schistosomiasis epidemiology, surveillance and clinical advantage. response with a focus in China Suitable for PhD or Honours students. • schistosomiasis vaccine development/deployment Diseases caused by intracellular protozoan parasites that • epidemiological studies and research to eliminate cause malaria and leishmaniasis require the generation echinococcosis in China through integrated control of CD4+ T (Th1) cells that produce pro-inflammatory approaches cytokines. These molecules stimulate dendritic cells (DCs) • ‘Magic Glasses’ Asia: Testing a video-based health and macrophages to expand CD4+ T cell responses educational intervention package for its impact on and activate phagocytes to kill captured or resident intestinal parasitic worm incidence, knowledge and pathogens. However, the inflammatory cytokines hygiene behaviour in primary school children in Asia. produced by Th1 cells also damage tissues, and as such, need to be tightly regulated. A downside of this regulation This research is supported by project and program grant is that it can allow parasites to persist and cause disease. funding from the National Health and Medical Research We identified unique gene signatures associated with Council of Australia, UBS Optimus Foundation of regulatory CD4+ T cell subsets and will test if molecules Switzerland, The Australian Infectious Disease Centre and associated with these signatures can be manipulated to the Chinese Government. improve responses to drug treatment and/or vaccines.
QIMR Berghofer 2021 – 2022 Student Projects 47 Human Malaria Immunology Group Team Head: Associate Professor Michelle Boyle +61 7 3845 3726 [email protected] https://www.qimrberghofer.edu.au/our- research/infectious-diseases/human- malaria-immunology/ Malaria is a disease of global importance, with >200 million cases and ~ 500,000 deaths annually. Alarmingly, malaria control has stagnated in recent years, highlighting the need for new control strategies including effective vaccines. The Human Malaria Immunology Laboratory aims to understand the development of protective immunity to malaria in order to inform vaccine design for at risk populations. We use human patient samples from populations living in malaria endemic areas, and from human volunteers deliberately infected with malaria parasites for our research. We have a particular focus on understanding the development of protective antibody responses to malaria, and the impact of age on immune development.
Single cell genomic technologies in human malaria immunology Projects can be adapted to suit Honours, Masters and PhD level students. Single cell genomic platforms off unprecedented ability to characterise heterogeneity of cell populations. We are applying single cell RNA and ATAC sequencing to understand human immune response to malaria infection. Our key goals are to identify key cellular subsets and responses that drive the induction of protective immunity. We use multiple human malaria cohorts, including controlled human malaria infection models, and cohorts of children and adults from different malaria transmission settings. This project will suit a student with a strong background in bioinformatics and/or computational biology who is interested in applying single cell technologies to human immunology.
48 QIMR Berghofer 2021 – 2022 Student Projects Chronic Disorders Program
QIMR Berghofer is researching a range of chronic disorders – complex conditions affecting the quality of life and health prospects of people around the world.
Demographic and lifestyle changes have led to a rise Conditions we research include: in the number of chronic disorders, and the Institute’s • Asthma and other • Eye disease research in this field is in response to the community’s allergies changing needs. • Heart disease • Biliary Atresia Chronic disorders researched at the Institute include • Hepatic fibrosis • Chronic obstructive asthma and other lung diseases, cardiovascular disease, • Infant nutrition and pulmonary disease cystic fibrosis, eye disease, haemochromatosis, chronic immunity liver disease and inflammatory bowel disease. Other work • Cystic fibrosis is focused on nutrition and maternal and infant health. • Inflammatory bowel • Endometriosis disease This wide-ranging research program includes identifying the genetic variation associated with the risk of some of • Iron-related conditions these disorders, as well as understanding disease progression and the basic molecular events that underlie the conditions.
QIMR Berghofer 2021 – 2022 Student Projects 49 CELLULAR & MOLECULAR BIOLOGY DEPARTMENT
prostate cancer. This project involves vesicle isolation Hepatic Fibrosis and characterisation, co-culture and imaging of prostate cancer and stromal cells in 2D and 3D, pathway analysis, Group and isolation of blood-derived vesicles for a potential Group Leader: biomarker. Professor Grant Ramm +61 7 3362 0177 MicroRNAs as ant-fibrotic agents [email protected] to treat liver scarring, fibrosis and cirrhosis in chronic liver disease https://www.qimrberghofer.edu.au/ our-research/chronic-disorders/hepatic- Projects can be adapted to suit Honours, PhD or fibrosis/ clinical students. The Hepatic Fibrosis Laboratory investigates the cellular Virtually all biological processes in eukaryotic cells are and molecular mechanisms of liver injury, scar tissue regulated by microRNAs that control protein-coding formation (fibrosis) and regeneration in chronic liver gene expression. Our laboratory has identified a number disease. If left untreated, uncontrolled fibrosis leads to of different microRNAs that regulate the expression of cirrhosis and liver cancer in adult liver diseases such as collagen in liver disease and that can be manipulated to haemochromatosis, viral hepatitis and non-alcoholic fatty control liver scarring or fibrosis. This project is designed liver disease, and in children in diseases such as cystic to generate novel, chemically modified microRNAs that fibrosis and biliary atresia. can be used as anti-fibrotic therapeutics to treat hepatic fibrosis and thus control the development of cirrhosis and Assessing the role of extracellular liver cancer in patients with chronic liver disease. vesicles in the progression and development of drug resistance in Anti-inflammatory small molecule prostate cancer inhibitor development to control liver inflammation associated with hepatic Co-supervisor: fibrosis in chronic liver disease Dr Carolina Soekmadji Projects can be adapted to suit Honours, PhD or +61 7 3362 0174 clinical students. [email protected] Inflammation is integral in driving early liver scarring (fibrogenesis). The association between hepatic This project can be adapted for PhD study, MPhil or inflammation and circulating ferritin levels in chronic Masters students. liver disease is well known. However, rather than simply acting as a marker of inflammation, our research has The development and progression of prostate cancer demonstrated that the H-subunit of Ferritin (FTH), are controlled by the androgen receptor (AR), a ligand- released upon hepatocellular injury, actually mediates regulated transcription factor. Current therapy for inflammation. This project will utilise state-of-the- advanced prostate cancer has focused on the inhibition or art molecular modelling techniques to identify FTH disruption of the AR signalling axis. Androgen deprivation binding sequences on cell surface receptors we have therapy (ADT) is focused on inhibiting the nuclear activity identified on liver fibroblasts that signal to the nucleus to of AR. While this is effective, ADT is associated with proinflammatory cytokines. Therapeutic small molecule multiple side effects including osteoporosis, decreased inhibitors will then be developed to treat chronic liver libido, and erectile dysfunction. Unfortunately, while this disease-inducing hepatic inflammation. treatment is initially effective in most patients, the tumour recurs in many patients within 2 years. Extracellular vesicles (EVs), such as exosomes, are vesicles secreted by cells to mediate communication with surrounding cells and can be isolated from blood. We recently discovered that EVs can influence the AR signalling axis in prostate cancer. This project aims to characterise the role of EVs and their cargo in regulating the development of
50 QIMR Berghofer 2021 – 2022 Student Projects CHRONIC DISORDERS PROGRAM
Iron Metabolism Molecular Nutrition Group Group Group Leader: Team Head: Professor Greg Anderson Associate Professor David Frazer +61 7 3362 0187 +61 7 3845 3063 [email protected] [email protected] https://www.qimrberghofer.edu.au/ https://www.qimrberghofer.edu.au/our- our-research/chronic-disorders/iron- research/chronic-disorders/molecular- metabolism/ nutrition/ The Iron Metabolism Laboratory studies a wide spectrum Dr David Frazer, Head of the Molecular Nutrition of iron-related issues from basic mechanisms of iron Laboratory, is passionate about iron and improving the homeostasis to disorders of iron metabolism. We are health of people with iron-related chronic diseases. particularly interested in iron nutrition, diseases of iron Whether that be from iron deficiency, iron insufficiency or loading (haemochromatosis, thalassaemia) and the having excess iron, such as in haemochromatosis. effects of iron on other conditions. To do this, we integrate Iron is a nutrient that is essential for the growth and genetic and molecular studies with biochemical and development of infants and children. It is necessary physiological approaches. Much of our recent research for healthy red blood cells, which move oxygen from has been based on understanding mechanisms of cellular the lungs throughout the body. Iron deficiency during iron transport and the way in which these processes are development can leave a permanent, life-long burden. regulated. The ultimate goal of our work is to improve Not only does it stunt growth and leave the child with a the diagnosis and treatment of iron related disorders. lack of energy, but also it can permanently impair brain A second major interest of our group is the use of function. nanotechnology to deliver drugs to treat iron loading disorders and other conditions, such as cancer. Whereas, having too much iron in the body can create another set of problems. One of the unexpected symptoms of haemochromatosis is early-onset arthritis.
QIMR Berghofer 2021 – 2022 Student Projects 51 Developing improved methods for assessing iron status Co-supervisor: Professor Greg Anderson & Associate Professor David Fraser Depending on the scope of the work selected, this project would be suitable as an Honours, Masters or PhD project. An adequate supply of iron is essential for normal health, and disturbances in iron metabolism represent a significant class of human diseases. Biochemical tests for measuring iron status are among the most frequently requested by doctors, but current methods for measuring body iron levels are far from ideal. The main limitation is that the most of the tests for measuring body iron are also influenced by inflammation. A good example of this is the serum ferritin test. As the incidence of obesity rises in our population, we are seeing more and more instances of high serum ferritin that are not related to high body iron. This is because obesity is an inflammatory condition. While correction of iron status using inflammation markers can be carried out, this is not always reliable and requires multiple tests to be conducted. The major goal of this project is to seek one or more robust and reliable marker/s of iron status that are not influenced by inflammation. A secondary goal is to develop a point of care assay based on this (or these) molecules. This project will consist of two main components. The first will be the discovery phase and will be carried out using mice. Using an experimental model like the mouse will enable us to precisely control conditions so that we can distinguish between iron-related effects and inflammation related effects. Animals will be maintained on diets of differing iron content, or subjected to various inflammatory stimuli (including a high fat diet). Plasma samples will be collected and analysed using a contemporary proteomics approach to seek differences between the various conditions. Depending on the initial results, we may also extend this to analyse the plasma metabolome. We will identify molecules that are influenced by iron status, but show little or no variation in response to inflammation. In the second part of the project, we will validate our findings by developing assays (likely immunoassays) for the molecules of interest and test them against a bank of human plasma samples taken from individuals whose iron status has been well-characterised using conventional tests. If time persists, we will optimise the assay for the most promising molecule with a view to developing a low cost point of care assay for iron status that requires only very small volumes of blood.
52 QIMR Berghofer 2021 – 2022 Student Projects CHRONIC DISORDERS PROGRAM
IMMUNOLOGY DEPARTMENT
Influence of early life parasitic infection Mucosal Immunology on infant gut microbiome Group This project is suitable for a PhD student. Team Head: Associate Professor The Western lifestyle, characterised by a nutrient-poor Severine Navarro diet, sedentary lifestyle, and exposure to antibiotics / [email protected] pollution, and the Hygiene Hypothesis have been directly implicated in the development of allergic diseases. https://www.qimrberghofer.edu.au/ Parasites, such as hookworms, modulate the microbiome our-research/chronic-disorders/mucosal- and provide important maturation signals to the immune immunology/ system that result in protection against allergy. We are The overarching theme of the Mucosal Immunology performing a cohort study on mothers and babies (up to Group is to promote immune regulation in order to control 2 years of age) from hookworm-endemic and hookworm- inappropriate immune responses responsible for allergy eradicated areas to determine the influence of intestinal and autoimmune diseases. We utilise experimental, parasites on the microbiome composition and the preclinical, and computational approaches to develop development of allergic diseases. This exciting project will novel therapeutic strategies that translate into preventative use a range of wet-lab, statistical and computational skills. or therapeutic interventions. Hookworm-derived polypeptides for the Prevention of allergy development treatment of chronic diseases in neonates by manipulating the This project is suitable for a Master, Honour or PhD microbiome student. This project is suitable for a PhD student. We have discovered hookworm proteins and peptides Nearly one billion people globally suffer from allergies able to modulate the immune response and protect responsible for significant morbidity and reduced quality against allergic and autoimmune diseases (like IBD and of life. Our group has discovered a process during the colitis). We are interested in developing these novel neonatal “Window of Opportunity” that prevents allergy compounds into the clinics and determine how the from developing later in life. We propose to understand proteins alter cellular function. Gut-resident dendritic the mechanisms that allow neonates to become cells are the primary target and epigenetic modifications resistant to allergen sensitisation. This project will allow are likely to occur. This project will use a range of us to develop a novel and revolutionary approach to immunological techniques (experimental models, flow the management of allergic diseases. We will use a cytometry, fluorescence imaging), proteomics approaches combination of experimental and clinical resources to (mass spectrometry), and single cell sequencing / address the role of the immune cells populating the gut metabolomics to characterise the mechanism of action. and gut-associated tissues, which will be visualised by Flow cytometry and fluorescence imaging. We will use techniques like metagenomic sequencing, metabolomics and proteomics to determine the interaction between the microbiome – intestinal epithelium – immune cells.
QIMR Berghofer 2021 – 2022 Student Projects 53 Microbiome and neonatal immune Respiratory development in early life Immunology Group The microbiome is known to affect immune development. Group Leader: Associate For example, germ-free mice have fewer Peyer’s patches Professor Simon Phipps in the gut wall, suggesting that the gut microbiome regulates the formation of this lymphoid tissue. Other +61 7 3362 0145 studies have shown that germ-free mice have fewer [email protected] natural killer T cells. Both the microbiome and the https://www.qimrberghofer.edu.au/our- immune system develop postnatally (predominantly if research/chronic-disorders/respiratory- not exclusively), and there is considerable bi-directional immunology/ crosstalk. In this project, we will study this relationship, with a focus on the seeding of innate lymphoid cells in The Respiratory Immunology Laboratory focuses on mucosal tissues such as the gut and the lungs. identifying pathogenic pathways that underpin the onset, progression, and exacerbations of asthma and chronic Eicosanoids and viral exacerbations of obstructive pulmonary disease. To achieve this, high- fidelity preclinical models of disease are developed that chronic obstructive pulmonary disease recapitulate key gene-environment interactions and allow (COPD) for elucidation of cellular and molecular mechanisms. Prostaglandin D2 is a lipid mediator generated from the Where possible, scientific findings are translated with ex metabolism of arachidonic acid. We recently discovered vivo model systems using primary human cells and by (Werder et al, Science Translational Medicine) that PGD2 analysing clinical material. can enhance or suppress the production of type III IFN, a potent antiviral cytokine. This contrasting effect is Insights into the influence of maternal dependent on the receptor subtype that is activated. diet on the severity of infant viral In both COPD and asthma, acute exacerbations (or bronchiolitis ‘attacks’) are associated with a respiratory infection, and in the setting of a viral infection, this has been associated Co-supervisor: with impaired production of type I and III IFNs. Here we Dr Ismail Sebina will investigate in clinical samples and in a preclinical model of COPD, whether PGD2 levels are elevated and +61 7 3362 0190 whether this mediator contributes to the loss in viral [email protected] control. We will also explore the molecular mechanism by which DP1 agonism promotes the production of innate Viral bronchiolitis is an infection of the small airways IFNs. (bronchioles) characterised by the infiltration of neutrophils, oedema, and shedding on the epithelial Cell death pathways and the induction cells that line the airway. A recent population study of type-2 inflammation found that the offspring of mothers who ate a poor diet It is now recognised that there are several different types in the third trimester were predisposed to severe viral of cells death. Importantly, the mode of cell death affects bronchiolitis. We have modelled this association in mice, the ensuing immune response. We have recognised an and established that the maternal diet affects the nascent important role for necroptosis in the induction of type-2 microbiome in the offspring and associated immune inflammation and immunity, which is the predominant development. This project will explore the cellular and module of immunity that underpins allergic diseases such molecular mechanisms by which the microbiome affects as asthma. In this project, we will employ experimental immune development and susceptibility to infection in the mouse models and in vitro culture models of primary lungs. airway epithelial cells to elucidate the molecular processes that initiate and regulate necroptosis.
54 QIMR Berghofer 2021 – 2022 Student Projects CHRONIC DISORDERS PROGRAM
GENETICS & COMPUTATIONAL BIOLOGY DEPARTMENT
PROJECT DESCRIPTION: Genetics, together with Statistical Genetics sun exposure, play an important role in the development of skin cancers. Our lab studies both melanoma and Group keratinocyte cancers. Melanoma is responsible for >1,800 Group Leader: deaths a year in Australia. While keratinocytic cancers are Professor Stuart MacGregor rarely deadly, their high incidence still results ~600 deaths are year, and are the most expensive cancer in Australia +61 7 3845 3563 (> $500 million p.a.). [email protected] https://www.qimrberghofer.edu.au/our- Through large cohort studies based at QIMR Berghofer research/chronic-disorders/statistical- Medical Research Institute, including the Queensland genetics/ Study of Melanoma: Environmental and Genetic Associations (Q-MEGA), the Queensland Twin Registry The Statistical Genetics Laboratory studies the role that (QTwin), and the QSkin skin cancer study (N ~ 20,000), genetic variation plays in determining risk of disease and from large international datasets (e.g. UK Biobank, N and its risk factors. The laboratory develops and applies > 500,000) we have a large body of data linking genetics statistical genetic methods to gene mapping studies to skin biology. Through this, we are able to assess the across a wide range of traits and diseases. genetics of skin cancers, skin ageing, pigmentation, and One major focus is understanding genetic and mole count. epigenetic variation in various cancers. Cancers studied AIMS: To use computational statistics approaches to include melanoma, ovarian cancer, breast cancer and identify risk factors for melanoma and keratinocytic cancer oesophageal cancer. Ultimately, this work will lead to a by leveraging related traits. To use this genetic information better understanding of why particular individuals are in risk prediction models and to identify factors important affected by cancer or why they respond poorly to a for outcome and prognosis. cancer treatment. APPROACHES: The project will focus on characterizing Another major interest is ophthalmological genetics, germline variation in skin cancer. Genome-wide data will with work ongoing to identify the specific genes involved be married with data on cancer susceptibility traits and in both eye disease and in underlying quantitative risk survival. The overlap of these traits will be explored to factors. identify new genetic risks common to all traits. Prediction models will be developed from this combined data, Genetics of skin cancer and calibrated against datasets in hand (e.g. Q-Skin) to determine their efficacy. Mendelian randomisation will be Co-supervisor: used to determine if potential risk factors associated with Associate Professor skin cancer are causal. Fine-mapping, bioinformatics, and Matthew Law post-GWAS approaches (e.g. gene-based tests) will be +61 7 3362 0213 used to fully interpret identified genetic variants. [email protected]
The post is ideally suited to someone with an undergraduate or Master’s degree in genetic epidemiology, epidemiology, statistics or bioinformatics. Experience in the analysis/manipulation of large datasets and a good knowledge of computing is desirable. Experience in cancer genetics and/or molecular biology advantageous but not essential. Non-statistical applicants must be able to demonstrate some knowledge of statistics. For statistical applicants, some knowledge of genetics is desirable.
QIMR Berghofer 2021 – 2022 Student Projects 55 Eye disease genetics B-lymphocytes in Associate Professor: Puya Gharahkhani Autoimmunity and +61 7 3362 0219 Malignancies Group [email protected] Discovering novel immunoregulatory Suited to someone with an undergraduate or Master’s molecules underlying the pathogenesis degree in genetic epidemiology, epidemiology, of systemic lupus erythematosus statistics or bioinformatics. Experience in the analysis/ manipulation of large datasets and a good knowledge Director and CEO: of computing is desirable. Experience in ophthalmic Professor Fabienne Mackay genetics advantageous but not essential. Non- statistical applicants must be able to demonstrate + 61 7 3362 0266 some knowledge of statistics. For statistical applicants, [email protected] some knowledge of genetics is desirable. PROJECT DESCRIPTION: Glaucoma is the leading Co-supervisor: cause of irreversible blindness worldwide. While there Dr Md Ashik Ullah is no cure once visual loss occurs, progressive visual +61 7 3845 3645 loss and blindness can usually be prevented by timely [email protected] treatment. This means early detection is vital. Unlike many other common complex diseases, the heritability of glaucoma is very high (70%) and traditional epidemiology This project is suitable for a Master, Honour or PhD studies have not identified any means by which risk can student. be decreased (e.g. via modifiable risk factors). The major The lab studies the immunobiology of B-lymphocytes role of genetic factors in glaucoma make understanding particularly the B cell survival factors BAFF and the molecular mechanisms fundamental to improve APRIL and their receptors BAFF-R, TACI and BCMA. screening and develop better therapies. Although Professor Mackay has shown that excess BAFF leads we have discovered many specific genes influencing to autoimmunity in mice and is associated with human glaucoma, we have also shown that most have still be to autoimmunity, in particular systemic lupus erythematosus be found (SLE). BAFF receptor TACI is highly expressed on memory AIMS: To identify more loci explaining why some people B cells in SLE patients and BAFF-TACI interactions leads get glaucoma and some do not. To translate genetic to heightened autoantibody production driving the disease findings into improved screening and into better therapies. pathology. Importantly, genetic deletion of TACI protects The project may also consider gene-mapping for other against SLE. However, the underlying mechanism remains eye diseases. largely unknown. In this project, we aim APPROACHES: We already have custody of very large- • To investigate the cellular mechanism by which scale genetic data sets (genome wide association studies, TACI signalling leads to exaggerated autoantibody exome/genome sequencing), with further data collection production in SLE. underway. The student will employ a range of statistical • TACI is known to regulate immunoglobulin A genetic approaches to interrogate these data and to production and alter gut microbiota. We will investigate determine the genes and pathways underlying glaucoma. how this altered gut microbiota and the metabolites are Statistical approaches for prediction will be investigated. associated with SLE disease severity. This project will use a range of immunological techniques (mouse models of experimental SLE, flow cytometry, confocal microscopy, ELISA), metagenomic sequencing, microbiome analysis and metabolomics to characterise the immunological mechanisms of action. We will validate the research findings using clinical samples.
56 QIMR Berghofer 2021 – 2022 Student Projects Mental Health Program In any year, approximately one in five (20.1%) Australians experience a mental illness, which significantly impact the individual, their friends and family, the health system and the economy.
Mental illnesses encompass disorders of mood, thinking, Our outstanding gains in the areas of psychiatric genetics, perception, communication and function. They can occur neuroimaging and neuroscience will inform novel throughout the lifespan and are disabling and distressing. strategies for prevention, early intervention and treatment Improving the mental health of Australians is critical of complex syndromes that affect the lives of so many and addressing the serious health challenge of mental Australians. disorders requires a focus on both strategies to prevent We research a variety of Mental Health and the onset of illness as well as improving the care and Neurological Disorders: treatment of those who are living with mental ill health. • Anxiety • Dementia The Mental Health program at QIMR Berghofer capitalises on broad expertise in neuroscience, genetic, • Attention Deficit • Depression Hyperactivity Disorder epidemiological and clinical research to expand the • Eating Disorders understanding of causes and treatments of mental illness. • Autistic Spectrum • Migraine Our Mental Health Research Teams work to conduct Disorder translational studies to make a meaningful difference to • Personality Disorders the health of Australians. • Bipolar Disorder • Schizophrenia We have a strong record in investigating innovative neuro-stimulation and psychopharmacological interventions, which are improving the lives of those individuals living with serious mental disorders.
QIMR Berghofer 2021 – 2022 Student Projects 57 GENETICS & COMPUTATIONAL BIOLOGY DEPARTMENT
The role of genomics in understanding Psychiatric psychiatric and neurological disease Genetics Group Project is suitable for PhD students only. Applicants Group Leader: with backgrounds in Psychology, Psychiatry, Statistics Professor Sarah Medland or Public Health are preferred. +61 7 3362 0248 Over the past decade, large-scale collaborative projects [email protected] have significantly increased our knowledge and understanding of the genetic risk factors for mental health https://www.qimrberghofer.edu.au/ and neurological conditions across the lifespan. our-research/mental-health/psychiatric- genetics/ Translation of genetic findings is usually conceptualised as a process involving the characterisation of implicated loci, Our research focuses on investigating the genetic and identification of treatment targets, drug development and environmental factors that influence mental health clinical trials. However, the accurate communication of the conditions and the impact of non-psychiatric conditions promises and limitations of new research findings is an on mental health. We work on many common mental essential part of research translation as is examining the health conditions and psychiatric traits including child and utility of analytic techniques such as polygenic risk scores. youth mental health, depression, anxiety and addiction. This project will focus on examining the ways genomic Assessing the cost and impact of data could be used in clinical practice and the accuracy Attention Deficit Hyperactivity Disorder and specificity of these techniques. The project will in Australia require a strong background in statistics and research methodology. Project is suitable for PhD students only. PROJECT DESCRIPTION: ADHD (defined as an Health and wellbeing in people with inability to focus, high levels of impulsivity and age- bipolar disorder inappropriate hyperactivity) is the most prevalent Project is suitable for PhD students only. childhood psychiatric disorder (affecting around 5% of children), with ~50% of those affected continuing to Bipolar disorder is a lifelong and severe psychiatric illness experience symptoms into adulthood. There is a high characterized by recurrences of episodes of depression level of comorbidity with other psychiatric disorders and and hypomania or mania. Lithium is a first option in the increased risks of incarceration, death and disability from pharmacotherapy of bipolar disorder. However, only one suicide, car accidents and misadventure. Using data third of patients have a good response to this treatment, from the census ADHD study a new richly-phenotyped i.e. they often recover and remain well as long as they nation-wide cohort of children with ADHD this project will continue taking Lithium. The rest have a partial or deficient examine the cost and impact of ADHD to families and the response. community. QIMR Berghofer is part of an international effort to The project will require a strong background in statistics identify individual differences in Lithium response. We and research methodology. Applicants with backgrounds are collecting data across Australia on mental health, in Psychology/Psychiatry, Statistics or Public Health are wellbeing and treatment response on bipolar disorder. preferred. We offer a project to analyse Lithium response in bipolar patients, comorbidity with other disorders and quality of Potential sub-projects include life. • Assessing the health service usage and financial costs of ADHD • Assessing the impact of ADHD on individual and family level psychological and social functioning • Assessing the level and types of side effects associated with ADHD medication
58 QIMR Berghofer 2021 – 2022 Student Projects MENTAL HEALTH PROGRAM
Identifying risk factors for problematic internet use and video Brain Modelling gaming in Australian adults Group Co-supervisor: Team Head: Associate Professor Dr Penelope Lind James Roberts +61 7 3845 3677 +61 7 3845 3850 [email protected] [email protected] https://www.qimrberghofer.edu.au/our- Suitable for Honours students only. This project is research/mental-health/brain-modelling/ most suitable for students with a strong background in The Brain Modelling Group models and analyses brain Psychology/Psychiatry and statistical analysis. structure and dynamics in health and disease. This The proliferation of computers, gaming consoles and work currently follows two major themes: developing widespread use of the internet in the last 15 years has new diagnostic methods for neonatal brain health and resulted in the emergence of behavioural addictions to modelling large-scale brain activity across the lifespan. digital technology, namely the internet and video games, In neonates, the group uses techniques from physics and the rise of cyberbullying. Pathological internet use and machine learning to extract more information than and video-gaming have been associated with mental ever before from intensive care monitoring of babies health issues (such as anxiety and depression), increased born prematurely. The goal is to enable early detection of rates of obesity, introversion, a high degree of loneliness, injuries and early prognosis of developmental outcomes, disrupted family relationships and academic problems. so that clinicians can optimise care with personalised Similarly, victims of cyberbullying can experience markers of brain health, potentially opening the window significant emotional and physical harm as well as social for new treatments. isolation. On the modelling side, the group is harnessing the I have previously recruited a cohort of Australian adults rapid developments in neuroimaging technology and who completed an online questionnaire in order to (i) connectomics to develop new mathematical models identify risk factors associated with these behaviours, (ii) of brain activity, in particular at the spatial scales most investigate the emotional and educational or occupational relevant to human health. The goal is to fill in some of impacts of these behaviours, and (iii) examine the co- the large gaps in our knowledge of how neuroimaging occurrence of these behaviours with other personality brain signals emerge from brain structure, on how this characteristics and psychopathologies such as substance relationship varies as we grow and age, and how things use and mental health disorders. can go wrong leading to neurological and psychiatric I offer a project to analyse the collected online disorders. questionnaire data, and to provide the Honours student access to the online questionnaire in order for them to Modelling brain dynamics across the potentially recruit a second cohort. lifespan. Suitable for PhD or Honours students. This project would suit students with a background in physics, maths, or a related discipline, and an interest in computational neuroscience, with some experience in programming (e.g. in MATLAB). A major challenge for neuroscience is to understand how the brain’s densely interconnected network of neurons— the “connectome”—gives rise to the rich repertoire of brain activity. The overarching aim of this project is to reveal how complex patterns of neural activity emerge from the connectome across the lifespan. This will entail using a novel combination of cutting-edge large- scale modelling of brain dynamics and state-of-the-art
QIMR Berghofer 2021 – 2022 Student Projects 59 neuroimaging data (both structural and functional). There will be numerous applications depending on interests, Translational examples include: how ageing brain structure changes our brain activity; how non-invasive brain stimulation Neurogenomics Group perturbs brain network activity; how disorders such as Group Leader: epilepsy, schizophrenia, or ADHD may emerge from Professor Eske Derks biologically-plausible changes to model parameters; how +61 7 3362 0169 flashing lights can drive nonlinear brain responses with [email protected] application to migraine; and developing novel analysis methods for complex spatiotemporal dynamics. https://www.qimrberghofer.edu.au/ our-research/mental-health/translational- neurogenomics/ Novel methods for monitoring brain activity in preterm babies The Translational Neurogenomics laboratory investigates the role of genetic factors in a range of psychiatric Co-supervisor: conditions, including schizophrenia, addiction, anxiety Dr Nathan Stevenson disorders and compulsive disorders. By researching a wide variety of symptoms that are typical of patients with +61 7 3845 3009 a particular psychiatric condition, they can use newly [email protected] developed statistical methods to discover associations between the condition and genetic variants. Suitable for PhD or Honours students. This project To fully identify and understand the biological processes would suit students with a background in physics, that result in a psychiatric condition, the lab: maths, statistics, machine learning, engineering, or a related discipline, with some experience in • studies genetic variation programming (e.g. in MATLAB). • identifies differences in gene expression levels A major challenge in neonatal intensive care is timely and observed in brain and non-brain tissues efficient bedside monitoring of the preterm brain to guide • finds associations between genetic risk and brain optimal individual care. The overarching aim of this project anatomy is to clinically validate novel methods to noninvasively detect acute brain injury and form a prognosis for long- Translational Neurogenomics refers to two topics that are term outcome as early as the first hours after preterm equally important in the study of psychiatric disorders: birth. Electroencephalography (EEG) is widely used to • the translation of genetic code to RNA and proteins monitor preterm brain health, but its diagnostic utility is limited by the need for subjective visual assessments of • the translation of research findings to the clinic (from raw signals or simple trends. These are also prone to bench to bed) the many recording artefacts in intensive care units. We recently developed new metrics for analysing preterm The interplay between environmental brain activity that enable detection of injuries and and genetic risk factors in the aetiology prediction of neurodevelopment, earlier than had been of substance use disorders possible before. This project will take the crucial next steps toward taking our new technology to the clinic. Co-supervisor: This will involve validating and refining our existing metrics Dr Zachary Gerring using a newly collected, large, multicentre dataset of preterm EEG with full clinical follow-up. There are also +61 7 3845 3006 numerous technical challenges to solve so that our [email protected] methods can work smoothly in the real-world intensive care environment. The outcome will be a validated brain Honours or PhD project. We are seeking a highly monitoring toolbox for neonatal intensive care, ready for motivated student with a strong interest in statistics immediate implementation in brain monitors. and quantitative studies. BACKGROUND: Mental health disorders (e.g., depression, anxiety, and substance use) are the leading
60 QIMR Berghofer 2021 – 2022 Student Projects MENTAL HEALTH PROGRAM
cause of global disease burden in the young adult Integrating genomic data to population. Twin and family studies show that both genetic characterise inherited risk factors for and environmental factors play a large role in the aetiology mental health disorders of these disorders. The Translational Neurogenomics group aims to identify genetic risk factors for a range of mental PhD or Honours project. We are seeking a highly health and substance use disorders, and investigate the motivated student with a strong interest in statistics interplay between genetic and environmental risk factors. and quantitative studies. UK Biobank is a major national and international health BACKGROUND: Mental health disorders, including resource with the aim of improving the prevention, depression, anxiety, and substance abuse disorders, diagnosis and treatment of a wide range of serious and life- afflict around half of individuals at some point in their lives threatening illnesses. UK Biobank recruited 500,000 people and account for a substantial proportion of the global aged between 40-69 years in 2006-2010 from across the burden of disease. Recently, significant progress has country to take part in this project. They have undergone been made in identifying genetic (i.e. inherited) risk factors measures, provided blood, urine and saliva samples for associated with mental health disorders through genome- future analysis, and detailed information about themselves wide association (GWA) studies of large, population- and agreed to have their health followed. Over many years, based cohorts. this will build into a powerful resource to help scientists Although these GWA studies have implicated many discover why some people develop particular diseases and genetic risk factors for mental health disorders, identifying others do not. Extensive information on mental health has the exact causal genes remains challenging. This is due been collected in a subset of 150,000 individuals. in part to complex interactions between multiple cellular POTENTIAL PROJECTS: data types in specific tissues that are likely to mediate susceptibility. Integrated studies of multiple cellular data, 1. Substance use and substance use disorders such as DNA sequence variation, gene expression, and (SUDs) are explained by a combination of genetic DNA methylation, in relevant tissues is therefore required and environmental factors. Exposure to traumatic to understand the impact of genetic risk factors in mental experiences, particularly in childhood, has been linked health. with both substance abuse and dependence. Is this link stronger in people with a genetic predisposition This project will use high quality gene expression to SUDs? This project will investigate the interaction and DNA methylation data measured whole blood to between genetic liability to substance use and traumatic characterise genetic risk factors underlying mental health experiences in the UK Biobank. disorders. Analyses will then be conducted across tissues using several publicly available multi-tissue genomic 2. A network approach to psychopathology is an compendia. This study will provide a unique resource to alternative way of conceptualising mental illness. A identify and characterise novel genetic factors underlying disorder is conceptualised as a system of interacting susceptibility to mental health disorders. The identification relationships between symptoms, rather than the set of such causal genes is the next crucial step in elucidating of symptoms resulting from a single latent factor (the the complex molecular pathways of mental health disorder). This project will conduct a network analysis of disorders and may help in the development of diagnostic substance use disorders (SUDs) using symptom-level tests and more rational treatment strategies. data from the UK Biobank. Networks will be estimated for groups with a high vs. low genetic predisposition for STUDY AIMS: substance use in order to determine whether genetic 1. to characterise genetic risk factors for psychiatric risk is associated with differences in psychopathological disorders in a large population-based sample network structure 2. to prioritise causal tissues and mechanisms using WHAT DO WE OFFER: independent multi-tissue genomic compendia • A position in a dynamic research environment and the WHAT DO WE OFFER: opportunity to conduct high-quality studies. • A position in a dynamic research environment and the • Access to large-scaled datasets through (inter)national opportunity to conduct high-quality studies. collaborations. • Access to large-scaled datasets through (inter)national • Being a part of a successful research team. collaborations.
QIMR Berghofer 2021 – 2022 Student Projects 61 Dissecting the genetic basis of Genetic clinical heterogeneity and differences Epidemiology Group in treatment response in patients with depression Team Head: Professor Nicholas Martin Co-supervisor: +61 7 3362 0278 Dr Miguel Renteria [email protected] +61 7 3845 3584 https://www.qimrberghofer.edu.au/ [email protected] our-research/mental-health/genetic- epidemiology/ RESEARCH STATEMENT: This project will The Genetic Epidemiology Laboratory seeks to identify characterise the genetic architecture that underlies the particular genes involved in complex disease variation in both symptom profiles and treatment aetiology. It performs longitudinal studies with twins on a response across patients with major depressive disorder wide range of complex traits of medical and behavioural (MDD). This will be achieved by applying a set of interest. Particular research over recent years has computational and statistical approaches to the analysis moved to genome wide association studies (GWAS) of a recently collected dataset of ~20,000 Australian to locate genes influencing complex traits including MDD patients who have answered a comprehensive anxiety, alcoholism, and dizygotic twinning. Most recently, online questionnaire and provided saliva samples for DNA the laboratory initiated projects to recruit large patient profiling. samples for GWAS of anorexia, depression and other BACKGROUND: MDD is a common complex disease psychiatric disorders. that results from genetic and environmental factors. It has a lifetime prevalence of ~15%, and is accompanied by considerable morbidity, excess mortality, and substantial social and economic costs. According to the World Health Organisation, it is currently the fourth leading cause of disability worldwide, and its prevalence is projected to rise in the upcoming years. Characterising the genetic architecture of major depression has been challenging, even compared to other psychiatric conditions such as schizophrenia and bipolar disorder. This is in part due to the highly heterogeneous and polygenic nature of MDD. A wide array of differences exists in symptom profiles, age of onset and triggers across patients. For instance, not all patients experience sleep dysfunction, fatigue or suicidal ideation in the same way. Importantly, patients respond differently to specific antidepressants. An antidepressant that is very effective for a patient might have adverse side effects in another one and vice versa. These differences arise due to multiple molecular pathways implicated in the genetic architecture of the disease.
62 QIMR Berghofer 2021 – 2022 Student Projects MENTAL HEALTH PROGRAM
Genetic and epidemiological studies of Identifying individuals at high risk of Parkinson’s disease Alzheimer’s disease
Suitable for PhD student and can be adjusted for Supervisor: Associate Professor Honours students. A background (or strong interest) Michelle Lupton in genetics, epidemiology, data science, statistics or bioinformatics is preferred. Previous research +61 7 3845 3947 experience coding and analysing data (genetic, clinical [email protected] or other kind) using R/Python is also desirable. Suitable for a PhD student with background in genetic BACKGROUND: Parkinson’s disease (PD) affects epidemiology, statistics and bioinformatics. Experience >100,000 Australians, and the number of patients in working with neuroimaging, DNA methylation or worldwide was estimated to be at least 6.1 million in whole genome/exome sequence data also desirable. 2016. In Australia, PD is the second most common neurological disorder, the second most common cause BACKGROUND: Dementia affects an estimated of dementia, and the fastest growing neurodegenerative 353,800 Australians, with up to 80% being diagnosed disease, with approximately 32 newly diagnosed patients with Alzheimer’s disease (AD). Despite a major research every day. PD is a progressive condition, typically defined effort, an effective treatment is not available. The by its motor features, which are also accompanied by pathogenic process of AD begins decades prior to the a range of non-motor symptoms. The onset, intensity clinical onset, so it is likely that treatments need to begin and progression of these clinical features varies greatly early in the disease process to be of benefit. from patient to patient and the underlying mechanisms AIM: To use known genetic and epigenetic risk factors of such heterogeneity are largely unknown, although it is to identify those at a high risk of developing AD, where a increasingly evident that genetics play an important role. high proportion of individuals will be in a prodromal stage AIM: We have collected self-reported measures on of AD. a range of sociodemographic, clinical and lifestyle APPROACH: To build on our current work using genetic variables from individuals with PD from all over Australia. risk prediction to identify individuals who are at high risk The aim of the study is to advance knowledge about of AD, a subset of which will be in a prodromal disease the environmental and genetic factors that contribute stage. To investigate both common and rare AD genetic to differences in Parkinson’s disease risk, clinical risk factors and test for associations with extensive heterogeneity, treatment response and progression. phenotypic data including neuroimaging and blood APPROACH: The student will conduct statistical and based methylation markers. Our group has access to computational data analyses aimed at identifying risk large highly phenotyped cohorts spanning different ages and protective factors (including genetic biomarkers) for and stages of dementia, including PISA (the Prospective Parkinson’s disease and its associated variables. Imaging Study of Ageing: Genes, Brain and Behaviour) based at QIMR Berghofer. OUTCOME: The characterization of risk and protective factors may provide important insights into the OUTCOME: The identification of individuals at high risk pathological mechanisms of PD development throughout of Alzheimer’s disease will provide: 1) important insights the lifespan, which is the first step toward developing into mechanisms of AD development throughout the life preventative and therapeutic interventions, including span; 2) the opportunity to investigate prodromal markers, disease-modifying therapies. and allow selection of individuals for early treatment strategies.
QIMR Berghofer 2021 – 2022 Student Projects 63 CELL & MOLECULAR BIOLOGY DEPARTMENT
Development of metal-based Cellular and therapeutics for neurodegenerative Molecular diseases PhD project but may also be considered for an Neurodegeneration Honours project. Group Biological trace elements, also known as trace minera, Group Leader: or biometals include copper, zinc, iron, selenium and Professor Anthony White manganese. These and other biometals have essential roles in many areas of brain function including energy +61 7 3362 0360 metabolism, transcription factor activity, antioxidant [email protected] regulation and synaptic signalling. During ageing and https://www.qimrberghofer.edu.au/ brain disease, regulation of biometals is dramatically our-research/mental-health/cellular-and- altered with changes to cellular and subcellular handling molecular-neurodegeneration/ and localization. This leads to impairment of brain cell function, in both neurons and surrounding cell types The Cellular and Molecular Neurodegeneration Laboratory (astroglia and microglia) and contributes to neuronal investigates the cause and potential treatments for cell death in disorders such as Alzheimer’s, Parkinson’s brain diseases including dementia (Alzheimer’s disease), and motor neuron diseases, as well as in lysosomal motor neuron disease (amyotrophic lateral sclerosis) and storage disorders such as Batten disease (childhood Parkinson’s disease. These disorders (collectively known brain disorder). Our research has uncovered some of as neurodegenerative diseases) are a growing health the processes involved in loss of biometal regulation and issue in Australia and worldwide, with few treatment found this to be an early event in many disorders. We options available. In order to gain a better understanding are also developing compounds that can help restore of these diseases and develop new therapeutic biometal stasis in the brain. approaches, the research team is currently developing new human brain cell culture methods. This project involves the investigation of new metal-based compounds as potential therapeutic or diagnostic agents A major focus of this research is the development of for Alzheimer’s disease and other brain disorders. These a 3D human ‘brain on a chip’ cell culture platform that compounds have unique properties including modulation combines different human brain cell types into a 3D of brain cell signalling, control of anti-oxidant function, microfluidic culture plate. The advantage is that the 3D and regulation of neuro-immune responses. The project system provides a far better model of the actual human examines the action of the compounds on a range of cell- brain while still allowing manipulation and experimentation types including animal and human neurons, astrocytes in a culture plate. and/or microglia, and we aim to understand the The cells used in the 3D brain on a chip include neurons, molecular pathways that contribute to therapeutic action. astrocytes and microglia (resident brain immune cells) Longer-term projects will involve the examination of the and are generated from human induced pluripotent stem compounds as therapeutics in specific animal models of cells, natural olfactory stem cells, and blood-derived cells brain disease to determine if they are suitable for further from normal people and those with brain disease. This therapeutic or diagnostic development towards the clinic. 3D platform is being used to build new models of the The wet lab project will utilize a range of tools and brain for dementia and motor neuron disease research, in techniques including brain cell culture, analysis of immune particular to understand the role of the immune system in response (cytokine analysis), phagocytosis assays, anti- brain diseases, and develop new therapeutic compounds oxidant assays, targeting the immune cells of the brain. X-ray analysis of biometal distribution and metalloproteomic studies on metal-protein interactions.
64 QIMR Berghofer 2021 – 2022 Student Projects MENTAL HEALTH PROGRAM
Generating patient-derived microglia to Olfactory stem cells for investigating investigate neuroinflammation in MND the causes and progression of This project will build important new tools for dementia understanding the role of the immune system in BACKGROUND: With no clinical success yet achieved amyotrophic lateral sclerosis (ALS), a form of motor neuron from amyloid-targeting strategies, there is an urgent need disease (MND). Inflammatory responses by resident brain to gain new insights and develop effective treatments and spinal cord immune cells (microglia) have an important for people who have dementia. New stem cell-based role in ALS/MND and are key targets for therapy. Until approaches have generated much excitement in now, research on microglia has been largely restricted to dementia research with the potential to study patient- cells from animal origin. We now have new techniques derived neurons and supporting cells. However the to generate microglia directly from ALS/MND patients commonly used ‘pluripotent’ stem cells are artificially to help understand the disease and test patient-specific generated and have major which make them unsuitable drugs to modulate the immune response in the brain and as tools to understand the disease process in the majority spinal cord. This project will provide a new approach to of late onset (sporadic) cases of dementia. investigating and treating inflammation in MND. Olfactory (nasal) tissue contains a unique population Generating Alzheimer’s microglia for of naturally occurring stem cells that renew the nasal receptor neurons and supporting cells in the nose testing patient responses to immune- throughout life. These exceptional stem cells can modulating compounds. be collected through a routine procedure with local Alzheimer’s disease is anticipated to affect 100 million anaesthetic and readily grown in a culture dish in a patients with an annual cost of US$1 trillion by 2050. laboratory to produce neurons and other key brain cell- Promising amyloid-clearing therapies have failed to types that accurately reflect the same types of brain cells translate to clinical outcomes, and new approaches that occur in the patient of origin. These cells provide a targeting the underlying molecular pathways of unique tool to study patient-specific disease processes Alzheimer’s disease are urgently required. There has and develop therapeutics for personalized dementia been a ‘re-awakening’ to the critical role of microglia in medicine. Alzheimer’s disease pathology. However, our ability to OBJECTIVE: Our plan is to collect nasal tissue from translate abnormal microglial biology into clinically relevant people with dementia and from people who are at a advances has been greatly impaired by inadequate high risk for dementia (together with matching control cell models. Microglia-like cells can now be routinely samples). The olfactory stem cells will be grown in our lab generated from human peripheral blood monocytes. and studied using a range of molecular approaches to The approach is cost-effective and rapid, and these provide unique insights into the early disease changes in a induced microglia reveal a remarkably close relationship person’s brain cells. We are also attempting to grow brain to mature human microglia in terms of cell surface marker ‘organoids’ from the stem cells. These are ‘mini-brains’ expression, functional assays, and gene expression. that represent the 3-dimensional structure of a small In this project we will generate microglia-like cells from part of a human brain and allow a much more accurate blood samples collected from Alzheimer’s patients, and understanding of how brain cells work (or fail to work) in people who are considered at high risk for Alzheimer’s dementia. This will enable us to understand how brain disease. We will compare the cultured microglia to identify cells are affected by dementia differently for each patient patient-specific immune abnormalities using a range (i.e. derived neurons will retain patient-specific epigenetic of assays currently established in our lab. We will then markers) and will allow the screening of potential screen individual patient microglia for efficacy of immune- therapeutic drugs on an individual basis. modulating compounds to identify effective patient- specific neurotherapeutics in ‘real-time’. This project will produce highly significant advances in patient-specific drug targeting for neuroinflammation in Alzheimer’s disease, leading to development of real-time, individual therapeutic approaches with major clinical benefit, including identifying patient-specific drugs, selection of suitable patients for clinical trials, and monitoring drug efficacy during trials.
QIMR Berghofer 2021 – 2022 Student Projects 65 Investigating blood-brain barrier neurodegenerative disorders and help in the development mediated drug delivery in of new BBB-permeable therapeutics to aid in the neurodegenerative diseases treatment of brain diseases.
Co-supervisor: 3D Alzheimer’s disease ‘brain on a chip’ Dr Lotta Oikari PhD project but may also be considered for an Honours. +61 7 3362 0375 [email protected] Alzheimer’s dementia is a rapidly growing health issue for Australia and worldwide with an expected 136 PhD project but may also be considered for Honours. million cases by 2050. The disease is characterized by accumulation of amyloid peptide and phosphorylated The blood-brain barrier (BBB) lines the walls of brain tau microtubule protein in the brain, together with an microvessels, and is critical in preventing the entry of abnormal inflammatory response and neuronal cell toxic molecules into the brain and enhancing the uptake death in affected brain regions. However, there is still little of nutrients. The BBB is formed by brain endothelial understanding of how these processes occur and why cells (BECs), pericytes and neural cells (neurons and they are age-dependent. One of the major problems with astrocytes) with BEC-expressed tight junction proteins trying to understand the disease and develop treatments (TJPs) and efflux transporters passively and actively, is that there are no ideal cell models to allow detailed respectively, inhibiting the entry of toxic molecules into molecular and cellular studies. the brain. The BBB is critical in protecting brain health, but it simultaneously challenges the delivery of drugs To overcome this, we are developing a 3D Alzheimer’s into the brain for the treatment of central nervous system disease ‘brain on a chip’ platform. We grow human neural disorders. In addition, neurodegenerative diseases, stem cells and human brain macrophages in 3D cultures including Alzheimer’s disease (AD) and amyotrophic on an OrganoPlateTM culture platform (Mimetas, leaders lateral sclerosis (ALS), are associated with an impaired in ‘organ on a chip’ technology). The aim is to generate BBB structure, highlighting the contribution of the BBB amyloid accumulation and tau phosphorylation together on disease pathophysiology. However, the majority with a neuro-immune response in the cultures more of our understanding of BBB structure and function is closely modelling the human Alzheimer’s brain (compared reliant on rodent models and given important species to 2D cultures of animal cells). These cultures can be differences, establishing a reliable in vitro model of the used to understand how amyloid and tau accumulate, human BBB is critical to increase our understanding of what role neuroinflammation has in the disease process, the human BBB in health and disease and aid in drug incorporation of patient cells, and enhance development delivery. As a promising approach, several protocols of potential therapeutics that would normally only be have been published in recent years for the generation of examined in large-scale animal studies. BECs (iBECs) from human induced pluripotent stem cells Techniques will include neural stem cell and inflammatory (hiPSCs). This allows for the scalable generation of BBB cell culture, molecular studies (i.e. cell transfections), cells and the study of disease-specific differences. microscopy (confocal imaging) and protein analysis Objective: In this project, we will generate iBECs from (western blot). patient-derived iPSCs to study differences in the BBB in neurodegenerative disorders compared to healthy controls. We will analyse differences in marker expression as well as functionality in iBECs to gain understanding into disease-specific effects. We will also analyse iBEC monolayer permeability using different compounds in single- and co-culture systems with other BBB cells to model drug delivery and to understand differences in the complete BBB system in a diseased brain compared to a healthy one. This project will be generate highly important information on how the human BBB is altered in neurodegenerative diseases and how this might affect therapeutic drug delivery. Findings from this project will contribute to a better understanding of human
66 QIMR Berghofer 2021 – 2022 Student Projects
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Dr Angela Trieu Graduate Development Coordinator +61 7 3845 3615 [email protected]
Marta Orlowska Graduate Development Assistant +61 7 3845 3554 [email protected]
[email protected] https://www.qimrberghofer.edu.au/ education/for-university-students/